Background

Compared with classic epidermal growth factor receptor (EGFR) mutations, uncommon EGFR alterations showed poorer outcomes in non-small-cell lung cancer (NSCLC) patients. This study aimed to investigate the efficacy and safety of PD-1/PD-L1 blockade and anti-angiogenesis treatments in NSCLC patients with uncommon EGFR mutations.

Methods

Twenty-one patients of NSCLC harboring rare EGFR mutations after previous treatments, including a platinum-based regimen and a targeted treatment (regardless of EGFR Ex20ins), were enrolled. Patients received sintilimab (anti-PD-1) combined with anlotinib (multi-target anti-angiogenesis). The primary endpoint was the objective response rate (ORR).

Results

At the data cut-off time (January 11, 2022), the median follow-up was 15.2 months. Among enrolled patients, twelve cases had EGFR Ex20ins and remaining nine cases had EGFR other mutations such as L861Q, G719A, and G709T. Patients harboring uncommon EGFR mutations exhibited a median progression-free survival of 6.7 months (95% CI, 2.4, 11.0), and the 6-month PFS rate was 52.4%. Moreover, of the nineteen patients evaluable for efficacy, the objective response rate (ORR) was 36.8% (7/19), and the disease control rates (DCR) was 84.2% (16/19). Notably, patients carrying EGFR Ex20ins showed similar ORR/DCR and PFS with other mutation patterns (ORR: 36.4% [4/11] vs. 37.5% [3/8], p=1.00; DCR: 90.9% [10/11] vs. 75.0% [6/8], p=0.348, PFS: 4.3 vs. 7.1 months, p=0.327). The most commonly observed grade 3 or greater treatment-related adverse events were hypertension (4.8%,1/21), immune-related pneumonitis (4.8%,1/21) and hand-foot syndrome (9.5%,2/21). Therefore, the use of sintilimab and anlotinib did not result in increased safety concerns.

Conclusions

Combination of sintilimab and anlotinib demonstrated durable efficacy and good tolerability in NSCLC patients with uncommon EGFR mutations. And further investigate is warranted to confirm this new chemo-free strategy.

Clinical trial identification

NCT04790409.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

EMB-01, a novel EGFR/cMET bispecific antibody with a unique co-degradation mechanism, demonstrates anti-tumor activities in EGFR and/or cMET driven tumor models. Here phase (ph) I results are described from the ongoing multicenter, Ph I/II study of EMB-01 in patients (pts) with advanced/metastatic solid tumors (NCT03797391).

Methods

Pts received EMB-01 (100-1600mg) IV weekly (QW) in 28-day cycles. Intensive PK was collected for all pts. Tumor assessments were performed by investigators per RECIST v1.1.

Results

As of August 20, 2021, 60 unselected (i.e., EGFR mutations or other gene aberrations unknown or unconfirmed) pts received EMB-01 (n=48 NSCLC, n=12 other solid tumors). Median age was 61 years, 51.7% were male, 60% were Asian. Median prior systemic therapies was 3. The most common (≥20%) all-grade (Gr) treatment-related AEs (TRAEs) were rash (66.7%), myalgia (63.3%), nausea (28.3%), paronychia (25.0%), alanine aminotransferase (ALT) increased and blood creatine phosphokinase (CK) MB increased (both 20.0%) with no infusion related reaction reported. Gr. 3 TRAEs included rash (8.3%), vomiting, GGT increase and alkaline phosphatase (ALP) increase (all 1.7%). PK was linear and drug exposures (AUC) were dose proportional at doses ≥500mg QW. Among 38 NSCLC response-evaluable pts, 2 had a partial response (PR) (1 confirmed), 14 had stable disease as the best response. The 2 PR pts included 1 with primary exon20ins disease and 1 with acquired resistance to a third-generation EGFR tyrosine kinase inhibitor (TKI). Disease control rate (DCR) was 42.1%. The longest duration of treatment was 73 weeks. 1600mg QW was determined as the RP2D.

Conclusions

The EMB-01 has a manageable safety profile consistent with EGFR and cMET inhibition. Preliminary anti-tumor evidence suggests EMB-01 can have activity in EGFR driven NSCLC, including pts with acquired EGFR TKI resistance and EGFR exon20ins mutations. The expansion phase (Ph II) is currently enrolling biomarker selected NSCLC pts with EGFR and/or cMET aberrations as identified by next-generation sequencing in circulating tumor DNA (ctDNA) and/or tumor tissue.

Clinical trial identification

NCT03797391; First release date was January 9, 2019.

Legal entity responsible for the study

Shanghai EpimAb Biotherapeutics Co., Ltd.

Funding

Shanghai EpimAb Biotherapeutics.

Disclosure

Z. Qing: Non-Financial Interests, Institutional, Principal Investigator: Shanghai EpimAb Biotherapeutics Co., Ltd.; Financial Interests, Personal, Other, Lecture and presentations fees: AstraZeneca; Financial Interests, Personal, Other, Lecture and presentations fees: Boehringer Ingelheim; Financial Interests, Personal, Other, Lecture and presentations fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Lecture and presentations fees: Eli Lilly; Financial Interests, Personal, Other, Lecture and presentations fees: MSD; Financial Interests, Personal, Other, Lecture and presentations fees: Pfizer; Financial Interests, Personal, Other, Lecture and presentations fees: Roche; Financial Interests, Personal, Other, Lecture and presentations fees: Sanofi. N. Gabrail: Non-Financial Interests, Institutional, Principal Investigator: Shanghai EpimAb Biotherapeutics Co., Ltd. D. Uprety: Non-Financial Interests, Institutional, Principal Investigator: Shanghai EpimAb Biotherapeutics Co., Ltd.; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Inc; Financial Interests, Personal, Advisory Board: Astrazeneca. J. Rotow: Financial Interests, Personal, Advisory Role, Consulting: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting: AbbVie; Financial Interests, Personal, Advisory Role, Consulting: Gritstone; Financial Interests, Personal, Advisory Role, Consulting: Lilly; Financial Interests, Personal, Advisory Role, Consulting: Takeda; Financial Interests, Personal, Advisory Role, Consulting: Sanofi-Genzyme; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Other, Honoraria: Jansen; Financial Interests, Personal, Other, Honoraria: Sanofi-Genzyme; Financial Interests, Personal, Other, Honoraria: Jazz; Financial Interests, Personal, Other, Honoraria: AstraZeneca. B. Han: Non-Financial Interests, Institutional, Principal Investigator: Shanghai EpimAb Biotherapeutics Co., Ltd. P.A. Jänne: Non-Financial Interests, Institutional, Advisory Role: Shanghai EpimAb Biotherapeutics Co., Ltd.; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Chugai Pharmaceuticals; Financial Interests, Personal, Advisory Role: Acea Biosciences; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: LOXO Oncology; Financial Interests, Personal, Advisory Role: Eli Lilly pharmaceuticals; Financial Interests, Personal, Advisory Role: Araxes pharmaceuticals; Financial Interests, Personal, Advisory Role: SFJ Pharmarceuticals; Financial Interests, Personal, Advisory Role: Voronoi; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Biocartis; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Takeda Oncology; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: Transcenta; Financial Interests, Personal, Advisory Role: Silicon Therapeutics; Financial Interests, Personal, Advisory Role: Syndax; Financial Interests, Personal, Advisory Role: Nuvalent; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Esai; Financial Interests, Personal, Advisory Role: Allorion Therapeutics; Financial Interests, Personal, Advisory Role: Accutar Biotech; Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: LOXO Oncology; Financial Interests, Personal, Funding, Research funding: Astellas Pharmaceuticals; Financial Interests, Personal, Funding, Research funding: AstraZenenca; Financial Interests, Personal, Funding, Research funding: Daiichi Sankyo; Financial Interests, Personal, Funding, Research funding: PUMA; Financial Interests, Personal, Funding, Research funding: Eli Lilly pharmaceuticals; Financial Interests, Personal, Funding, Research funding: Boehringer Ingelheim; Financial Interests, Personal, Funding, Research funding: Revolution Medicines; Financial Interests, Personal, Funding, Research funding: Takeda Oncology; Financial Interests, Personal, Royalties, Post-marking royalities from Dana Farber: LabCorp; Other, Institutional, Other, Cancer Institute owned intellectual property on EGFR mutations licensed to LabCorp: LabCorp. M. Nagasaka: Financial Interests, Personal, Speaker’s Bureau: Takeda; Financial Interests, Personal, Speaker’s Bureau: Blueprint Medicine; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Caris Life Sciences; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Jansssen; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Mirati Therapeutics; Financial Interests, Personal, Invited Speaker, Travel support: AnHeart. M. Zheng: Non-Financial Interests, Institutional, Member, Investigator: Shanghai EpimAb Biotherapeutics Co., Ltd. Y. Zhang: Financial Interests, Personal, Full or part-time Employment: Shanghai EpimAb Biotherapeutics Co., Ltd. G. Yang: Financial Interests, Personal, Full or part-time Employment: Shanghai EpimAb Biotherapeutics Co., Ltd. Y. Sun: Financial Interests, Personal, Full or part-time Employment: Shanghai EpimAb Biotherapeutics Co., Ltd. B. Peng: Financial Interests, Personal, Full or part-time Employment: Shanghai EpimAb Biotherapeutics Co., Ltd. Y. Wu: Financial Interests, Institutional, Other, Contract: AstraZeneca; Financial Interests, Institutional, Other, Contract: Boehringer Ingelheim; Financial Interests, Institutional, Other, Contract: Bristol Myers Squibb; Financial Interests, Institutional, Other, Contract: Hengrui; Financial Interests, Institutional, Other, Contract: Roche; Financial Interests, Personal, Advisory Role, Consulting fees: AstraZeneca; Financial Interests, Personal, Advisory Role, Consulting fees: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting fees: Novartis; Financial Interests, Personal, Advisory Role, Consulting fees: Takeda; Financial Interests, Personal, Advisory Role, Consulting fees: MSD; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Beigen; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: MSD; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Novartis; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Pfizer; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Roche; Financial Interests, Personal, Speaker’s Bureau, Not promotional activities: Sanofi.

Background

Exposure to osimertinib (osi), a 3^rd generation TKI for treatment of non-small cell lung cancer (NSCLC) and a sensitizing epidermal growth factor receptor (EGFR) mutation is variable between patients (pts). We evaluated the boosting capacity of cobicistat (cobi), a strong Cytochrome P450 3A (CYP3A)-inhibitor, on osi exposure in pts with NSCLC and low osi plasma trough concentration.

Methods

This was a pharmacokinetic, proof-of-concept, multicenter clinical trial (NCT03858491). Pts with NSCLC treated with osi were eligible when their steady state osi plasma trough concentration was low (<195 ng/mL) and they did not use any CYP3A-affecting drugs/products. On day 1, the area under the plasma concentration-time curve (AUC_0-24,ss) of osi and its metabolite (AZ5104) were calculated using a limited sampling strategy. Cobi treatment (150 mg QD) was started on day 2. After three weeks of combined use, a second AUC_0-24,ss of osi and AZ5104 was determined. Cobi dose could be escalated if the osi trough concentration was still <195 ng/mL and no toxicity was reported. The primary endpoint was the increase in osi exposure and the secondary endpoint was toxicity. Cobi could be continued during the expanded access phase, with additional follow-up of osi exposure within 2 – 4 months after the last AUC_0-24,ss.

Results

In total 11 pts were included and cobi addition led to an increase in osi exposure in all 11 pts. The mean increase in total AUC_0-24ss (AUC_0-24ss osi + AUC_0-24ss AZ5104 combined) was 60%, (range 19%-192%), with 73% (19% - 192%) and 38% (21% - 52%) for female and male pts, respectively. The increase in total AUC_0-24ss was mainly driven by an increase of the osi AUC_0-24ss, while AZ5104 AUC_0-24ss remained largely similar, as the proportion of AZ5104 of the total AUC_0-24ss decreased from 10% (baseline) to 7% (boost). Three pts underwent dose-escalation of cobi (150 mg BID (n = 3) and 150 mg QID (n = 1)), but no definitive effect was observed. The boosting effect of cobi was consistent over time and no grade ≥2 toxicity was observed.

Conclusions

Pharmacokinetic boosting of osi with cobi in pts with NSCLC was feasible without increasing toxicity, while a wide variation in boosting was seen.

Clinical trial identification

NCT03858491.

Legal entity responsible for the study

The author.

Funding

ZonMW (the Netherlands Organisation for Health Research and Development).

Disclosure

The author has declared no conflicts of interest.

Background

We report outcomes for tepotinib – a highly selective, potent MET inhibitor – in patients (pts) with MET exon 14 (METex14) skipping in VISION Cohorts A (primary analysis) and C (confirmatory), by prior therapies. These are relevant for clinical practice, given the CHMP positive opinion (Dec 2021) for tepotinib in patients with advanced NSCLC harboring METex14 skipping, previously treated with immunotherapy (IO) and/or platinum-based chemotherapy (CT).

Methods

Pts with advanced/metastatic METex14 skipping NSCLC received 500 mg (450 mg active moiety) tepotinib once daily. Safety was assessed in all pts who received tepotinib, and efficacy in pts with ≥3 months’ follow-up (data cut-off: Feb 1, 2021). Primary endpoint was objective response by IRC (RECIST 1.1).

Results

Of 275 pts evaluable for efficacy, 138 were previously treated (+2L): median age 70.9 years (range, 41–89), 51% female, 40% smoking history, 42.0% enrolled in Europe. 86% of +2L pts had prior platinum-based CT, 53% had prior IO (37% as monotherapy, 15% had IO-CT). Objective response rate (ORR) was 44.2% (95% CI: 35.8, 52.9), with median duration of response (mDOR) of 11.1 (8.4, 18.5). Disease control rate was 75.4% (67.3, 82.3), and median overall survival (mOS) was 19.9 months (15.8, 22.3). Efficacy was observed regardless of prior therapies (Table). 137 pts were treatment-naïve (1L): median age 74.6 years (range, 47–94), 50% female, 53% smoking history, 60.6% enrolled in Europe. ORR was 54.0% (45.3, 62.6) and mOS was 17.6 months (13.4, 29.7). Overall, pts with brain metastases at baseline (51/275 [18.5%]) had systemic ORR of 52.9% (38.5, 67.1), and mDOR of 9.0 months (5.6, ne). Treatment-related adverse events (TRAEs) were mostly mild-moderate across therapy lines; Grade ≥3 TRAEs occurred in 33.1% of 1L pts and 25.9% +2L pts. Safety profile was similar in pts with prior IO. Table: 24P

Conclusions

Tepotinib demonstrated robust and durable clinical activity across treatment lines, and in pts with brain metastases. TRAEs were mostly mild-moderate.

Clinical trial identification

NCT02864992.

Editorial acknowledgement

Medical writing assistance (funded by Merck Healthcare KGaA, Darmstadt, Germany) was provided by Syneos Health, London, UK.

Legal entity responsible for the study

Merck Healthcare KGaA, Darmstadt, Germany.

Funding

Merck Healthcare KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

Disclosure

F. Griesinger: Other, Personal, Advisory Role: AstraZeneca, Roche/Genentech, Pfizer, Boehringer Ingelheim, MSD, Bristol Myers Squibb, Celgene, Takeda, AbbVie, Novartis and Bayer; Other, Personal, Other, Receives honoraria: Roche/Genentech, Boehringer Ingelheim, Pfizer, AbbVie, MSD, Bristol Myers Squibb, Ipsen, Novartis and AstraZeneca; Other, Institutional, Funding, Receives research funding (institution): AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Celgene, Lilly, Novartis, Pfizer, Roche and Takeda. E. Felip: Other, Personal, Advisory Role: Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol Myers Squibb, Guardant Health, Novartis, Takeda, AbbVie, Blue Print Medicines, Lilly, Merck Healthcare KGaA, Darmstadt, Germany, MSD, Janssen and Samsung; Other, Personal, Speaker’s Bureau, Receiving speaker’s bureau honoraria : Pfizer, Roche, AstraZeneca, Bristol Myers Squibb, Novartis, Takeda, Lilly, MSD, Medscape, prIME Oncology and Touchtime; Other, Personal, Funding, Receives research funding: Fundación Merck Salud and Grant for Oncology Innovation (GOI); Other, Personal, Member of the Board of Directors, Independent member on the Board of Directors: Grifols. E.F. Smit: Other, Personal, Advisory Role, Receives honoraria (institution) for his advisory/consultancy role: Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol Myers Squibb, Merck Healthcare KGaA, Darmstadt, Germany, MSD Oncology, Takeda, Bayer, Regeneron, Novartis, Daiichi Sankyo and Seattle Genetics; Other, Personal, Funding, Receives research funding (institution) : Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca and Bristol Myers Squibb. R. Veillon: Other, Personal, Advisory Role: MSD, Pfizer and Novartis; Other, Personal, Speaker’s Bureau, Receives speakers’ bureau honoraria: MSD, Bristol Myers Squibband Roche; Other, Personal, Funding, Receives research funding: Roche, Takeda, AbbVie, Merck Healthcare KGaA, Darmstadt, Germany and Bristol Myers Squibb. J. Raskin: Other, Personal, Advisory Role: Pfizer, Lilly; Other, Personal, Invited Speaker: Boehringer Ingelheim, Bristol Myers Squibb; Other, Personal, Other, Travel expenses: Roche. M. Thomas: Other, Personal, Other, Reports honoraria for scientific meetings and travelling support: Bristol Myers Squibb, MSD, AstraZeneca, Novartis, Roche, Takeda, Lilly, Chugai, Celgene, Boehringer Ingelheim and Pfizer; Other, Personal, Advisory Board, Advisory board honoraria: Bristol Myers Squibb, MSD, AstraZeneca, Novartis, Roche, Takeda, Lilly, Boehringer Ingelheim and Pfizer; Other, Institutional, Funding, Research funding (institution): Bristol Myers Squibb, AstraZeneca, Roche and Takeda. P. Conte: Other, Personal, Funding, Research funding: Novartis, Roche and Merck Healthcare KGaA, Darmstadt, Germany; Other, Personal, Speaker’s Bureau, Speaker’s bureau fees: Novartis, AstraZeneca and Roche; Other, Personal, Other, Travel expenses: Celgene, Novartis, AstraZeneca and Tesaro. D. Kowalski: Other, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Pfizer and Roche/Genentech. L. Paz-Ares: Other, Personal, Leadership Role: ALTUM Sequencing and Genomica; Other, Personal, Other, Honoraria: Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, Ipsen, Lilly, EMD Serono, an affiliate of Merck KGaA, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier and Takeda; Other, Personal, Speaker’s Bureau: AstraZeneca, Bristol Myers Squibb, Lilly, EMD Serono, an affiliate of Merck KGaA, MSD Oncology, Pfizer and Roche/Genentech; Other, Institutional, Funding, Research funding: AstraZeneca, Bristol Myers Squibb, Kura Oncology, MSD and PharmaMar; Other, Personal, Other, Travel, accommodations and expenses: AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche and Takeda; Other, Institutional, Other, Other relationships: Amgen, Ipsen, Novartis, Pfizer, Roche, Sanofi, Merck Healthcare KGaA, Darmstadt, Germany and Servier. G. Garcia Ledo: Other, Personal, Other, Consulting: Natera; Other, Personal, Speaker’s Bureau, Speaker´s bureau fees: Bristol Myers Squibb, Merck Sharp and Dohme. F. de Marinis: Other, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, MSD Oncology, Pfizer and Roche/Genentech. A. Scherz: Other, Institutional, Advisory Role: AstraZeneca, Bristol Myers Squibb, Takeda and MSD. K. Berghoff: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany. R. Bruns: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany; Financial Interests, Personal, Stocks/Shares: Merck Healthcare KGaA, Darmstadt, Germany. G. Otto: Financial Interests, Personal, Full or part-time Employment: Merck Healthcare KGaA, Darmstadt, Germany; Financial Interests, Personal, Stocks/Shares: Novartis. P. Paik: Other, Personal, Advisory Role: AbbVie, AstraZeneca, Calithera, Celgene, Lilly, Takeda, EMD Serono, an affiliate of Merck KGaA, Xencor, Bicara, Boehringer Ingelheim and GlaxoSmithKlein; Other, Institutional, Funding, Received research funding (institution): Celgene and EMD Serono, an affiliate of Merck KGaA.

Background

Tepotinib is an oral, once daily (QD), highly selective, potent MET inhibitor, that has shown durable activity in METex14 skipping advanced NSCLC. Here, we report outcomes in Asian patients (pts) from VISION; these data are relevant to clinical practice as tepotinib is approved in several Asian countries; Japan, Taiwan, South Korea, Singapore, and is available in Hainan, China.

Methods

Pts with advanced METex14 skipping NSCLC, detected by liquid (L+) and/or tissue (T+) biopsy, received tepotinib 500 mg (450 mg active moiety) QD. Primary endpoint was objective response by IRC; secondary endpoints included disease control (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Results

VISION enrolled 106 Asian pts (38 in Japan, 20 in South Korea, 12 in Taiwan, 30 in China, 6 outside Asia). At data cut-off (Feb 1, 2021), 79 pts had ≥3 months’ follow-up and were assessed for efficacy (38% were female, 42% had smoking history, 34% were treatment-naïve [1L], 82% had adenocarcinoma, 72% were T+). Objective response rate (ORR) was 54.4% (95% CI: 42.8, 65.7), median (m) DOR was 18.5 months (8.3, not estimable [ne]), mPFS was 12.1 months (6.9, ne), and mOS was 20.4 months (19.1, ne). Meaningful activity was observed across therapy lines (Table). In 1L T+ pts (n=20), ORR was 70.0% (45.7, 88.1) with 83% 12-m DOR rate, 74% 12-m PFS rate, 67% 24-m OS rate (medians ne). In +2L T+ pts (n=37), ORR was 51.4% (34.4, 68.1), mDOR was 8.3 months (4.3, ne), mPFS was 11.1 months (5.6, ne), and mOS was 26.8 months (14.3, ne). At data cut-off, 88 pts received tepotinib and were analyzed for safety. Most common adverse events (AEs) were peripheral edema, creatinine increase, and diarrhea. 29.5% of pts had Grade ≥3 treatment-related (TR) AEs. TRAEs led to dose reduction in 29.5%, temporary interruption in 43.2%, permanent discontinuation in 14.8% of pts. Table: 25P

Tepotinib efficacy (IRC) in Asian patients

Conclusions

In VISION, tepotinib showed robust and durable clinical activity, with a tolerable safety profile, in Asian pts with METex14 skipping NSCLC.

Clinical trial identification

NCT02864992 (VISION).

Editorial acknowledgement

Medical writing assistance (funded by Merck Healthcare KGaA, Darmstadt, Germany) was provided by Syneos Health, London, UK.

Legal entity responsible for the study

Merck Healthcare KGaA, Darmstadt, Germany.

Funding

Merck Healthcare KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

Disclosure

J.C. Yang: Other, Institutional, Advisory Role, Advisory or consultancy services: Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, MSD, Novartis, Roche/Genentech, Takeda Oncology, Yuhan Pharmaceuticals, Ono Pharmaceuticals and Pfizer; Other, Institutional, Funding, Research funding to institution: Eli Lilly, JNJ, Puma Technology, Gilead, GSK, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, MSD, Novartis, Roche/Genentech, Takeda Oncology and Yuhan Pharmaceuticals; Financial Interests, Institutional, Advisory Role, Institutional fee for advisory or consultancy services and grant: AstraZeneca. H. Sakai: Financial Interests, Institutional, Speaker’s Bureau, Speakers’ bureau fees: Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., AstraZeneca, Chugui Pharma, Taiho Pharmaceutical, Boehringer Ingelheim and Merck Healthcare KGaA, Darmstadt, Germany. M. Morise: Financial Interests, Institutional, Speaker’s Bureau, Speakers’ bureau fees: Chugai, MSD, ONO and AstraZeneca. T. Kato: Financial Interests, Institutional, Research Grant, Grants during conduct of the study: Merck Biopharma, an affiliate of Merck KGaA; Other, Institutional, Research Grant, Grants outside the submitted work: Regeneron; Other, Personal and Institutional, Research Grant, Grants and personal fees: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Chugai, Eli Lilly, Merck Biopharma, an affiliate of Merck KGaA, MSD, Novartis, Ono, Pfizer, Taiho and Boehringer Ingelheim; Other, Personal, Other, Personal fees: Daiichi Sankyo, Nippon Kayaku and Takeda. J. Han: Financial Interests, Institutional, Funding, Research funding: Hoffmann-La Roche Ltd, ONO, Pfizer and Takeda; Other, Institutional, Advisory Role, Consulting/advisory role: AstraZeneca, Bristol Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Takeda, Medpacto, Abion and ONO; Other, Institutional, Other, Honororia: AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, Merck Sharpe & Dohme and Takeda. J. Huang: Financial Interests, Institutional, Full or part-time Employment, Employee of Merck Healthcare KGaA, Darmstadt, Germany: Merck Healthcare KGaA. K. Berghoff: Financial Interests, Institutional, Full or part-time Employment, Employee of Merck Healthcare KGaA, Darmstadt, Germany.: Merck Healthcare KGaA. R. Bruns: Financial Interests, Institutional, Full or part-time Employment, Employee of Merck Healthcare KGaA, Darmstadt, Germany: Merck Healthcare KGaA; Financial Interests, Personal, Stocks/Shares, Mr Bruns holds stock in Merck Healthcare KGaA, Darmstadt, Germany: Merck Healthcare KGaA. G. Otto: Financial Interests, Institutional, Full or part-time Employment, Employee of Merck Healthcare KGaA, Darmstadt, Germany.: Merck Healthcare KGaA. X. Le: Financial Interests, Institutional, Advisory Board, Consulting or advisory role: AstraZeneca, Eli Lilly and EMD Serono, an affiliate of Merck KGaA; Financial Interests, Institutional, Funding, Research funding: Eli Lilly and Boehringer Ingelheim. P. Paik: Other, Institutional, Advisory Role, Advisory role: AstraZeneca, Calithera, Lilly, Takeda, EMD Serono, an affiliate of Merck KGaA, Xencor, Bicara, Boehringer Ingelheim, Xencor and CrownBio; Financial Interests, Institutional, Other, Research institution has received research expenses: Celgene, EMD Serono, an affiliate Merck KGaA, Boehringer Ingelheim and Bicara. All other authors have declared no conflicts of interest.

Background

Capmatinib is a selective MET inhibitor, approved for patients (pts) with METex14 metastatic NSCLC. Its efficacy and safety have been reported for Tx-naive and pretreated pts from the multicohort phase II GEOMETRY mono-1 study. Here we provide primary efficacy data from Cohort 7, as additional first-line (1L) data, in Tx-naive pts with METex14 aNSCLC.

Methods

GEOMETRY mono-1 enrolled pts into several cohorts. Cohorts 5b (mature data previously presented) and 7 comprised Tx-naive pts with METex14 NSCLC. Evaluated outcomes included: Overall response rate (ORR; primary endpoint), median duration of response (mDOR), and median progression-free survival (mPFS), all by blinded independent central review; median overall survival (mOS); and adverse events (AEs). Data cutoff: Aug 30, 2021.

Results

In Cohort 7, 32 Tx-naive pts received capmatinib 400 mg twice daily. ORR was 68.8% (95% CI, 50.0-83.9), with mDOR of 16.59 months (95% CI, 8.34-not estimable [NE]). mPFS was 12.45 months (95% CI, 6.87-20.50) and mOS was not reached yet. Efficacy results for the 2 Cohorts of Tx-naive pts are shown in the table. In Cohort 7, AEs of any grade, regardless of causality, occurred in 31 pts (96.9%), including 26 pts (81.3%) with grade 3/4 AEs. Tx-related AEs (TRAEs) occurred in 29 pts (90.6%), including 18 (56.3%) with grade 3/4; TRAEs led to dose adjustment/interruption in 23 pts (71.9%) and Tx discontinuation in 6 (18.8%) pts. Common TRAEs (≥20%, all grades) were peripheral edema (59.4%), nausea (37.5%), and increased blood creatinine (28.1%). Peripheral edema led to Tx discontinuation in 2 pts (6.3%). Table: 26P

Conclusions

Primary efficacy analysis for Cohort 7 confirms previous findings from Cohort 5b in Tx-naive pts with METex14, showing an ORR of ∼70% and mPFS of >1 year. Safety data are consistent with previously published data for all pts. These data continue to support the use of capmatinib for 1L Tx of pts with METex14 aNSCLC.

Clinical trial identification

NCT02414139.

Editorial acknowledgement

Azka Ashraf, of Chameleon Communications, London, UK, provided medical writing assistance, which was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceutical Corporation.

Disclosure

J. Wolf: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Blueprint, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; Financial Interests, Personal, Invited Speaker: Bayer, Chugai; Financial Interests, Institutional, Research Grant: BMS, Janssen, Novartis, Pfizer. E.B. Garon: Financial Interests, Personal, Other, Consulting or advisory role: ABL Bio; Financial Interests, Personal, Other, Consulting or advisory role: Boehringer Ingelheim; Financial Interests, Personal, Other, Consulting or advisory role: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting or advisory role: Dracen Pharmaceuticals; Financial Interests, Personal, Other, Consulting or advisory role: Eisai; Financial Interests, Personal, Other, Consulting or advisory role: Eli Lilly; Financial Interests, Personal, Other, Consulting or advisory role: EMD Serono; Financial Interests, Personal, Other, Consulting or advisory role: Gilead; Financial Interests, Personal, Other, Consulting or advisory role: GSK; Financial Interests, Personal, Other, Consulting or advisory role: Merck; Financial Interests, Personal, Other, Consulting or advisory role: Natera; Financial Interests, Personal, Other, Consulting or advisory role: Novartis; Financial Interests, Personal, Other, Consulting or advisory role: Personalis; Financial Interests, Personal, Other, Consulting or advisory role: Regeneron; Financial Interests, Personal, Other, Consulting or advisory role: Sanofi; Financial Interests, Personal, Other, Consulting or advisory role: Shionogi; Financial Interests, Personal, Other, Consulting or advisory role: Xilio Therapeutics; Financial Interests, Institutional, Other, Grant / Research support: ABL Bio; Financial Interests, Institutional, Other, Grant / Research support: AstraZeneca; Financial Interests, Institutional, Other, Grant / Research support: Bristol Myers Squibb; Financial Interests, Institutional, Other, Grant / Research support: Dynavax Technologies; Financial Interests, Institutional, Other, Grant / Research support: EMD Serono; Financial Interests, Institutional, Other, Grant / Research support: Genentech; Financial Interests, Institutional, Other, Grant / Research support: Iovance Biotherapeutics; Financial Interests, Institutional, Other, Grant / Research support: Eli Lilly; Financial Interests, Institutional, Other, Grant / Research support: Merck; Financial Interests, Institutional, Other, Grant / Research support: Mirati Therapeutics; Financial Interests, Institutional, Other, Grant / Research support: Neon Therapeutics; Financial Interests, Institutional, Other, Grant / Research support: Novartis. H.J.M. Groen: Financial Interests, Institutional, Funding, Grants or contracts : Boehringer Ingelheim; Financial Interests, Institutional, Other, Consulting fees: Novartis; Financial Interests, Institutional, Other, Consulting fees: Eli Lilly; Financial Interests, Institutional, Other, Consulting fees: Boehringer Ingelheim; Financial Interests, Institutional, Other, Consulting fees: Merck; Financial Interests, Institutional, Other, Consulting fees: Bristol Myers Squibb. D.S.W. Tan: Financial Interests, Institutional, Funding, Research funding: AstraZeneca; Financial Interests, Institutional, Funding, Research funding: Pfizer; Financial Interests, Institutional, Funding, Research funding: ACM Biolabs; Financial Interests, Institutional, Funding, Research funding: Amgen; Financial Interests, Personal, Other, Consulting / advisory role: Pfizer; Financial Interests, Personal, Other, Consulting / advisory role: Novartis; Financial Interests, Personal, Other, Consulting / advisory role: Takeda; Financial Interests, Personal, Other, Consulting / advisory role: Boehringer Ingelheim; Financial Interests, Personal, Other, Consulting / advisory role: Merck; Financial Interests, Personal, Other, Consulting / advisory role: Amgen; Financial Interests, Personal, Other, Consulting / advisory role: AstraZeneca; Financial Interests, Personal, Other, Consulting / advisory role: DKSH; Financial Interests, Personal, Other, Consulting / advisory role: Roche; Financial Interests, Personal, Other, Consulting / advisory role: C4 Therapeutics; Financial Interests, Personal, Other, Consulting / advisory role: GSK. A. Robeva: Financial Interests, Personal, Full or part-time Employment: Novartis. M. Carbini: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Other, Participation on a Data Safety Monitoring Board or Advisory Board : Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. A. Yovine: Financial Interests, Personal, Full or part-time Employment: Novartis. R. Heist: Financial Interests, Personal, Other, Consulting: Novartis; Financial Interests, Personal, Other, Consulting: Daichii Sankyo; Financial Interests, Personal, Other, Consulting: EMD Serono; Financial Interests, Personal, Other, Consulting: AbbVie; Financial Interests, Institutional, Funding, Research funding to institution: AbbVie; Financial Interests, Institutional, Funding, Research funding to institution: Agios; Financial Interests, Institutional, Funding, Research funding to institution: Corvus; Financial Interests, Institutional, Funding, Research funding to institution: Incyte; Financial Interests, Institutional, Funding, Research funding to institution: Novartis; Financial Interests, Institutional, Funding, Research funding to institution: Lilly; Financial Interests, Institutional, Funding, Research funding to institution: Mirati; Financial Interests, Institutional, Funding, Research funding to institution: Turning Point; Financial Interests, Institutional, Funding, Research funding to institution: Daichii Sankyo. All other authors have declared no conflicts of interest.

Background

Selpercatinib, a first-in-class highly selective and potent CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ NSCLC. In prior reports, follow-up was limited and duration of response (DoR) and progression-free survival (PFS) were ongoing and immature.

Methods

Updated analysis of selpercatinib in pts with RET fusion+ NSCLC in LIBRETTO-001 (NCT03157128) was conducted with a 15-month (mo) interval between the preceding and current analyses. Primary endpoint was objective response rate (ORR, RECIST 1.1) by independent review committee (IRC). Secondary endpoints included DoR, PFS, clinical benefit rate (CBR; CR+PR+SD ≥16 weeks), OS, and safety.

Results

Efficacy results from treatment naïve pts (N=69) and pts previously treated with platinum chemotherapy (N=247) are shown (Table). Despite a median follow-up (f/u) of ∼24 mo in the treatment naïve and platinum chemotherapy pretreated populations, median DoR (mDoR) and PFS (mPFS) estimates are still not mature. Among all NSCLC pts, 26 had measurable CNS metastases at baseline per IRC. Selpercatinib treatment resulted in a CNS ORR of 84.6% (95% CI: 65.1–95.6), with a CNS mDoR of 9.4 mo (95%CI: 7.4–15.3) at a median f/u of 25.8 mo. In the safety population (NSCLC pts with ≥ 1 dose, N=356), the most common adverse events (AEs in ≥25% pts) were dry mouth, diarrhea, hypertension, increased ALT/AST, peripheral edema, constipation, rash, headache, and fatigue. In total, 34 pts (9.6%) discontinued treatment due to AEs, including 11 pts (3.1%) due to drug-related AEs per investigator. Table: 27P

Conclusions

With longer follow-up and additional patients, selpercatinib demonstrates durable efficacy and intracranial activity regardless of line of therapy. The safety profile of selpercatinib remains consistent with prior reports.

Clinical trial identification

NCT03157128.

Editorial acknowledgement

Medical writing assistance was provided by Kristi Gruver, an employee of Eli Lilly and Company.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

A. Drilon: Financial Interests, Personal, Advisory Board, Honoraria/Advisory Boards: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Onco; Financial Interests, Institutional, Research Grant, Associated research paid to institution: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Financial Interests, Personal, Research Grant: Foundation Medicine; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, Food/Beverage: Merck, Puma, Merus, Boehringer Ingelheim; Financial Interests, Personal, Other, CME Honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Clinical Care Options, EPG He. V. Subbiah: Financial Interests, Personal, Research Grant, Grant/Research Support: National Institutes of Health grant R01CA242845, Loxo Oncology/Eli Lilly, Novartis, Bayer, Berghealth, Incyte, Fujifilm, PharmaMar, D3, Pfizer, Multivir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Med; Financial Interests, Personal, Advisory Board, Advisor/Board Member: Helsinn, Loxo Oncology/Eli Lilly, R-Pharma US, INCYTE, QED Pharma, MedImmune, Novartis. O. Gautschi: Financial Interests, Personal, Other, Consultant; all honoraria paid to institution: Amgen and Lilly, advisory boards for AstraZeneca, Merck, Amgen and Lilly. P. Tomasini: Financial Interests, Personal, Expert Testimony, Honoraria for expert testimony: AstraZeneca, Roche, Takeda, JNJ, AbbVie, Bristol Myers Squibband BI. F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Healthcare Research & Pharmacoepidemiology, Merck Group, ACCMED, Nadirex, MSD, Pfizer, Servier, Sanofi, Roche, Amgen, Incyte, Dephaforum; Financial Interests, Personal, Advisory Board, Consultant or advisory board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, Bristol Myers Squibb, Menarini, Astra Zeneca; Financial Interests, Personal, Principal Investigator: Novartis, F.Hoffmann-LaRoche Ltd, Bristol Myers Squibb, Ignyta Operating INC, MSD Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, DAICHI SANKIO Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag I. B. Solomon: Financial Interests, Personal, Advisory Board, Advisory Boards/Honoraria: Eli Lilly, Pfizer, Roche/Genentech, Novartis, Takeda, AstraZeneca, Merck Sharpe Dohme, Bristol Myers Squibb, Amgen, BeiGene. D. Shao-Weng Tan: Financial Interests, Personal, Other, Honoraria: Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda; Financial Interests, Personal, Advisory Board, Advisory/Consultancy: Novartis, Bayer, Boehringer Ingelheim, Celgene, Astra Zeneca, Eli-lily, Loxo, GlaxoSmithKlein, MSD; Financial Interests, Institutional, Research Grant, Research grant/funding to institution: Novartis, Astra Zeneca, Bayer, Pfizer, Amgen. J. Wolf: Financial Interests, Personal, Advisory Board, Advisory boards and lecture fees: Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; Financial Interests, Institutional, Research Grant, Research support to institution: Bristol Myers Squibb, Janssen Pharmaceutica, Novartis, Pfizer. K. Park: Financial Interests, Personal, Advisory Board, Advisor: Eli Lilly and Company. K. Goto: Financial Interests, Personal, Research Grant: Eli Lilly and Company, Japan KK; Financial Interests, Personal, Advisory Board, Advisory/Consultancy, and Honoraria: Eli Lilly and Company and Japan KK. V. Soldatenkova: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. S. Szymczak: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. S. Barker: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. T. Puri: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. A.B. Lin: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. H.H.F. Loong: Financial Interests, Personal, Advisory Board: Boehringer-Ingelheim, Celgene, Eli Lilly, Illumina, Novartis, Merck Sereno, Takeda, George Clinical; Financial Interests, Personal, Speaker’s Bureau: AbbVie, Bayer, Eisai, Eli Lilly, Guardant Health, Novartis; Financial Interests, Personal, Other, Travel Support: Bayer, Boehringer-Ingelheim, MSD, Novartis, Pfizer; Financial Interests, Personal, Research Grant, Research funding: MSD, Mundipharma, Novartis; Financial Interests, Personal, Other: Member, Pharmacy and Poisons (Registration of Pharmaceutical Products and Substances: Certification of Clinical Trial/Medicinal Test) Committee, Pharmacy & Poisons Board of Hong Kong. B. Besse: Financial Interests, Personal, Other: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche-Genen. All other authors have declared no conflicts of interest.

Background

The phase 1/2 ARROW (NCT03037385) study supported approval of pralsetinib, a highly potent oral selective RET inhibitor, for RET-altered non-small cell lung cancer (NSCLC) in the US, EU, and other countries, and thyroid cancer (TC) in the US. Here we report data from the phase 1 dose-escalation part of ARROW.

Methods

In phase 1, pralsetinib once daily (QD; 30–600 mg) or twice daily (BID; 200/100 mg or 100/100 mg) was assessed in advanced solid tumors (RET-altered for doses >120 mg per day). Key endpoints were maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety (all primary); PK and overall response rate (ORR) (both secondary).

Results

At data cut-off (November 18, 2019), 60 of 62 patients enrolled in phase 1 were included in the dose-determining population (QD, n=51; BID, n=9); 2 who received <75% of study drug with no dose-limiting toxicities (DLTs) were excluded. Median age was 56.5 years (range 19‒85), 58% were male, and 61% had Eastern Cooperative Oncology Group Performance Status 1. Median time to maximum plasma concentration of pralsetinib was 2–3 hours at 30–600 mg QD. Mean plasma elimination half-life was 11–23 hours at 200–400 mg QD; steady state was reached with <3-fold accumulation, consistent with half-life and dosing frequency. Exposure at 400 mg QD sustained coverage above predicted 90% inhibitory concentration for RET in tumor and brain. ORR was 42% (95% confidence interval 15‒72) in 12 patients treated at 400 mg QD (RET-fusion positive NSCLC [n=3], differentiated TC [n=2], and medullary TC [n=6 RET-mutant, n=1 unknown mutation status]). DLTs occurred in 11 patients, including 2/4 at 600 mg QD (hypertension, hyponatremia), 2/12 at 400 mg QD (hypertension, myositis), 2/11 at 300 mg QD (hypertension, tumor lysis syndrome [TLS]), 2/4 at 200/100 mg BID (both hypertension), and 2/5 at 100/100 mg BID (hypertension, TLS). Based on safety and exposure, 400 mg QD was chosen as MTD and RP2D. Six patients discontinued due to treatment-related adverse events.

Conclusions

Pralsetinib 400 mg QD was well tolerated, showed promising antitumor activity, and was chosen as the RP2D for the registrational phase 2 part of ARROW.

Clinical trial identification

NCT03037385.

Editorial acknowledgement

Medical writing was provided by Mhairi Foster, PhD, and editorial assistance by Travis Taylor, BA, both of Paragon, Knutsford, UK, supported by Blueprint Medicines Corporation, Cambridge, MA.

Legal entity responsible for the study

Blueprint Medicines Corporation.

Funding

Blueprint Medicines Corporation.

Disclosure

J.F. Gainor: Financial Interests, Personal, Full or part-time Employment: Ironwood Pharmaceuticals; Financial Interests, Personal, Full or part-time Employment, Immediate family member who is an employee of Ironwood Pharmaceuticals: Ironwood Pharmaceuticals; Financial Interests, Personal, Advisory Role, Consulting or advisory role: Agios, Amgen, Array BioPharma, Blueprint Medicines Corporation, Bristol Myers Squibb, Genentech, Gilead Sciences, Jounce Therapeutics, Lily, Loxo, Merck, Moderna Therapeutics, Oncorus, Regeneron, Takeda, and Theravance; Financial Interests, Personal, Stocks/Shares: Ironwood Pharmaceuticals; Financial Interests, Personal, Other, Honoraria: ARIAD, Incyte, Merck, Novartis, Pfizer, and Takeda; Financial Interests, Personal, Funding: Adaptimmune, Alexo Therapeutics, ARIAD, Array BioPharma, AstraZeneca, Bristol Myers Squibb, Genentech, Jounce Therapeutics, Merck, Novartis, and Tesaro. M. Taylor: Financial Interests, Personal, Advisory Board, Consultant/Advisory Board: Bristol Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines Corporation, Novartis, Sanofi/Genzyme, and Pfizer; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Eisai, and Merck; Financial Interests, Institutional, Funding: ArQule, Bristol Myers Squibb, Bayer, Sanofi, Array BioPharma, Loxo, Blueprint Medicines Corporation, Novartis Pharma SAS, Eisai Europe Ltd. S.I. Ou: Financial Interests, Personal, Other, Consultant Honorarium: Lilly, Pfizer, BeiGene, Daiichi Sankyo, Silverback Therapeutics, Astra Zeneca, Elevation Oncology, and JNJ/Janssen; Financial Interests, Personal, Stocks/Shares: Turning Point Therapeutics and Elevation Oncology. E. Garralda: Financial Interests, Personal, Other, Consulted and/or had advisory role: Roche, Ellipses Pharma, NeoMed, Janssen, Boehringer Ingelheim, Seattle Genetics, TFS, Alkermes, Thermo Fisher Scientific, and Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: MSD, Roche, and Thermo Fisher Scientific; Financial Interests, Personal, Other, Travel and accommodation expenses : Bristol Myers Squibb, Menarini, Glycotrope GmbH, and MSD; Financial Interests, Institutional, Funding: Novartis, Roche, and Thermo Fisher Scientific. M.S. Brose: Financial Interests, Personal, Other, Consultant/Advisory Board: Eisai, Loxo, Bayer, Blueprint Medicines Corporation; Financial Interests, Personal, Funding: Loxo/Lilly, Bayer, Blueprint Medicines Corporation. J. Parepally: Financial Interests, Personal, Full or part-time Employment: Blueprint Medicines Corporation; Financial Interests, Personal, Stocks/Shares: Blueprint Medicines Corporation. H. Zhang: Financial Interests, Personal, Full or part-time Employment: Blueprint Medicines Corporation; Financial Interests, Personal, Stocks/Shares: Blueprint Medicines Corporation. C. Rahal: Financial Interests, Personal, Full or part-time Employment: Blueprint Medicines Corporation; Financial Interests, Personal, Stocks/Shares: Blueprint Medicines Corporation. A. Zalutskaya: Financial Interests, Personal, Full or part-time Employment: Blueprint Medicines Corporation; Financial Interests, Personal, Stocks/Shares: Blueprint Medicines Corporation. V. Subbiah: Financial Interests, Personal, Funding, Research funding/grant support for clinical trials: AbbVie, Agensys, Inc., Alfasigma, Altum, Amgen, Bayer, BERG Health, Blueprint Medicines Corporation, Boston Biomedical, Inc., Boston Pharmaceuticals, Celgene Corporation, D3 Bio, Inc., Dragonfly Therapeutics, Inc., Exelixis, Fujifilm, GlaxoSmithKlein, Ide; Financial Interests, Personal, Other, Travel support: ASCO, ESMO, Helsinn Healthcare, Incyte Corporation, Novartis, and PharmaMar; Financial Interests, Personal, Other, Consultancy/advisory board: Helsinn Healthcare, Incyte Corporation, Loxo Oncology/Eli Lilly, MedImmune, Novartis, QED Therapeutics, and R-Pharm US; Financial Interests, Personal, Other: Medscape.

Background

In ALTA-1L planned interim analyses, BRG progression-free survival (PFS) by blinded independent review committee (BIRC) was superior to CRZ. We report final ALTA-1L (NCT02737501) results.

Methods

Patients (pts) were randomized 1:1 to BRG 180 mg qd (7-day lead-in at 90 mg) or CRZ 250 mg bid. Primary endpoint: PFS by BIRC. Secondary endpoints included intracranial PFS (iPFS; BIRC), overall survival (OS), safety, quality of life (QoL).

Results

275 pts randomized (BRG/CRZ, n=137/138); median age 58/60 y; prior chemotherapy (CT) 26%/27%; median CT duration, 71/73 days; baseline brain metastases (BL BM) 29%/30%. As of 29 Jan 2021 (last patient contact), median follow-up was 40.4/15.2 mo, with 166 (73/93) PFS events. BIRC PFS hazard ratio (HR) was 0.48 (95% CI: 0.35–0.66, log-rank P<0.0001); median PFS was 24.0 (95% CI: 18.4–43.2)/11.1 (9.1–13.0) mo; 3-yr PFS rate, 43%/19%. PFS HR by investigator was 0.43 (0.31–0.58; median PFS 30.8 vs 9.2 mo). Median duration of response (DoR) was 33/14 mo by BIRC and 37/11 mo by investigator. Median OS was not reached in either group (events: 41/51; HR 0.81 [0.53–1.22]; 3-yr OS 71%/68%. In pts with BL BM, PFS HR 0.25 (0.14–0.46); OS HR 0.43 (0.21–0.89; Table). Most common grade ≥3 treatment-emergent adverse events (AE): BRG: increased creatine phosphokinase (26%) and lipase (15%), hypertension (14%); CRZ: increased alanine aminotransferase (10%), lipase, (8%), aspartate aminotransferase (7%). Any-grade interstitial lung disease/pneumonitis: 5.9%/2.2%; discontinuation due to AE: 13.2%/8.8%. Median time to worsening in pt-reported global health status/QoL was 26.7/8.3 mo; HR 0.69 (0.49–0.98). Table: 29P

Conclusions

BRG demonstrated durable overall and intracranial efficacy with manageable tolerability with extended treatment, confirming BRG as a standard of care in treatment-naive ALK+ NSCLC.

Clinical trial identification

NCT02737501; Release date: March 30, 2016.

Editorial acknowledgement

Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Legal entity responsible for the study

ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Funding

ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Disclosure

M. Tiseo: Other, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Roche; Other, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Pierre Fabre, Roche. S. Popat: Other, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Guardant Health, Janssen, Lilly, Merck KGaA, Novartis, Roche, Takeda; Financial Interests, Institutional, Other, Sub-investigator: Amgen, MSD; Financial Interests, Institutional, Other, Coordinating PI: Ariad, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Takeda, Turning Point Therapeutics; Financial Interests, Institutional, Other, Local PI: AstraZeneca, GlaxoSmithKlein, Roche, Trizel; Other, Personal, Advisory Board: ALK Positive UK, International Association for the Study of Lung Cancer, Lung Cancer Europe, Ruth Strauss Foundation; Other, Personal, Leadership Role: British Thoracic Oncology Group, European Thoracic Oncology Platform; Other, Personal, Officer: European Society of Medical Oncology; Other, Personal, Member of the Board of Directors: Mesothelioma Applied Research Foundation. H.R. Kim: Financial Interests, Personal, Other, Honoraria, consulting or advisory role: AstraZeneca, Roche, Boehringer Ingelheim. M. Ahn: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, MSD, Novartis; Other, Personal, Other, Consulting or advisory role: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, MSD, Novartis. J.C. Yang: Financial Interests, Personal and Institutional, Other, Personal and institutional fees for advisory or consultancy services: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, MSD, Novartis, Roche Genentech, Takeda Oncology, Yuhan Pharmaceuticals,; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Other, Advisory or consultancy services: Eli Lilly; Financial Interests, Personal, Other, Advisory or consultancy services: Ono Pharmaceuticals, Pfizer; Financial Interests, Institutional, Other, Institutional fee for advisory or consultancy services: JNJ, Puma Technology, Gilead, GSK. J. Han: Financial Interests, Personal, Funding, Research funding: Roche. M.J. Hochmair: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, MSD, Pfizer, Roche, Takeda; Other, Personal, Other, Consulting or advisory role: Boehringer Ingelheim, MSD, Novartis, Roche, Takeda. K.H. Lee: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Eli Lilly, Boehringer Ingelheim; Other, Personal, Advisory Board: AstraZeneca, Eli Lilly, Boehringer Ingelheim. A. Delmonte: Other, Personal, Other, Consulting or advisory role: AstraZeneca, Boehringer Ingelheim. M.R. Garcia Campelo: Other, Personal, Other, Consulting or advisory role: Takeda, AstraZeneca, Roche, Pfizer, Bristol Myers Squibb, Boehringer Ingelheim, Pfizer, Janssen, Eli Lilly. D. Kim: Financial Interests, Institutional, Funding, Research funding: Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge B. F. Griesinger: Other, Personal, Other, Consulting or advisory role: ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Siemens, Amgen, GSK, Janssen. E. Felip: Other, Personal, Other, Consulting or advisory role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Guardant Health, MSD, Novartis, Pfizer, Roche, Takeda, Merck. R. Califano: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Roche, MSD, Boehringer Ingelheim, Takeda, Bayer, Sanofi and Novartis; Other, Personal, Other, Consulting or advisory role: AstraZeneca, Bristol Myers Squibb, Roche, MSD, Boehringer Ingelheim, Takeda, Bayer, Sanofi and Novartis. A.I. Spira: Other, Personal, Other, Consulting or advisory role: ARIAD, AstraZeneca, Clovis Oncology, Roche, Amgen, Mirati, Bristol Myers Squibb, Merck. S.N. Gettinger: Other, Personal, Other, Consulting or advisory role: ARIAD, Bristol Myers Squibb, Janssen; Other, Personal, Funding, Research funding: ARIAD, AstraZeneca/MedImmune, Bristol Myers Squibb, Boehringer Ingelheim, Incyte, Pfizer, Roche/Genentech. H.M. Lin: Financial Interests, Personal, Full or part-time Employment: Takeda. Y. Liu: Financial Interests, Personal, Full or part-time Employment: Takeda. F. Vranceanu: Financial Interests, Personal, Full or part-time Employment: Takeda. D.R. Camidge: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Takeda, Arrys/Kyn, Genoptix, Mersana Therapeutics, Roche/Genentech, Ignyta, Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med, Orion, Clovis, Celgene, Novartis; Financial Interests, Personal, Other, Honoraria, DSMB: G1 Therapeutics; Financial Interests, Personal, Other, Honoraria, ILD adjudication committee: Daiichi Sankyo; Financial Interests, Personal, Funding, Research funding: ARIAD/Takeda.

Background

SY-3505 is a third-generation Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) against both wild-type and a broad range of mutations occurring in first-generation and second-generation ALK inhibitor-resistant patients. This First-in-human phase I study is to investigate the safety, pharmacokinetics (PK) and clinical efficacy of SY-3505 in Chinese ALK-positive advanced non-small cell lung cancer (NSCLC) patients.

Methods

Eligible Patients in this multi-center, open-label phase I study (CTR20191702) were administered orally with SY-3505 (25,50,100,200,300,400,500,600 or 800mg) once daily. Primary endpoints included safety, tolerability, maximum tolerated dose (MTD), dose limited toxicities (DLTs) and RP2D. Secondary endpoints included preliminary efficacy and PK parameters.

Results

Between Apr.26, 2020 and Dec.31, 2021, totally 32 ALK+ NSCLC patients including 2 (6.25%) ALK TKI-naive and 30 (93.75%) previously treated with ALK inhibitors were enrolled into 9 dose escalation cohorts (n=24) and 2 dose expansion cohorts (500mg/600mg, n=8). Totally, 22 (68.7%) of 32 patients experienced treatment-related adverse events (TRAEs), and grade 3-4 TRAEs were observed in 1 (3.12%) patient. One DLT (grade 3 diarrhea) was occurred in the 800mg dose cohort. The most common TRAEs (>10% frequency) were diarrhea (all grade 25.00%; grade 3-4 3.12%), nausea (all grade 15.63%; grade 3-4 0.00%), vomiting (all grade 15.63%, grade 3-4 0.00%), aspartate aminotransferase elevation (all grade 12.50%; grade 3-4 0.00%). Tumor regression was observed in 18 (64.30%) of 28 assessable patients who had received at least one ALK TKI. PK analyses indicated the accumulation of SY-3505 in the patients with an approximately t_1/2 of 26-56 hours. RP2D will be identified based on the safety, PK parameters and anti-tumor activity in dose-expansion period.

Conclusions

SY-3505 was well tolerated in patients including those previously treated with two or more ALK TKIs, and most of the TRAEs were minor and reversible. Preliminary anti-tumor activity was also observed in patients who had received more than one first or second-generation ALK TKI. The dose-expansion phase of this study is ongoing.

Clinical trial identification

CTR20191702.

Legal entity responsible for the study

Shouyao Holdings (Beijing) Co., Ltd.

Funding

Shouyao Holdings (Beijing) Co., Ltd.

Disclosure

Y. Sun: Financial Interests, Personal and Institutional, Full or part-time Employment: Shouyao Holdings (Beijing) Co., Ltd. All other authors have declared no conflicts of interest.

Background

Chemotherapy remains the standard-of-care for most patients with advanced NSCLC. Utidelone, a genetically engineered epothilone analogue, demonstrated marked and durable antitumor activity in patients with metastatic breast cancer. Here, we reported the efficacy and safety of utidelone for advanced NSCLC refractory to second-line treatment.

Methods

This was an open label, multicenter, phase II study (NCT03693547). Eligible criteria included age 18-70, ECOG performance status of 0-1, failure of previous standard second-line treatment (including platinum-containing chemotherapy with or without targeted therapy). All patients received the recommended dose of utidelone (40mg/m²/d intravenously on d1-d5, 21d per cycle). The primary endpoint was objective response rate (ORR). Safety was analyzed in all patients who received at least one dose of study treatment.

Results

From April 22, 2019 to January 22, 2021, 26 patients were enrolled, with a median age of 55.3 (range 39-68) years. 61.5% of patients had an ECOG PS of 1, 80.8% had adenocarcinoma, and 65% were pre-treated with taxol. At baseline, pre-treatment in the second-line, third-line, and fourth-line or over were present in 34.6%, 38.5%, and 26.9%, respectively. Efficacy was evaluated in full analysis set (FAS) (n=26) and per protocol set (PPS) (n=21) with an ORR of 15.4% (95% CI 4.4, 34.9) and 19.0% (95% CI 5.4, 41.9), respectively. DCR were 69.2% (95% CI 48.2, 85.7) and 81.0% (95% CI 58.1, 94.6) in FAS and PPS, respectively. The median PFS was 4.37 (95% CI 2.50 5.29) months in FAS and 4.37 (95% CI 2.50, 9.76) months in PPS. OS was not reached but 12 month-OS rate was 69.0% (95% CI 45.1%, 84.1%) in FAS and 71.0% (95% CI 42.7%, 87.1%) in PPS. 26 (100%) patients had at least one adverse event (AE), 2 (7.7%) experienced discontinuation of utidelone and 8 (30.8%) had a dose reduction. Common grade 3-4 AEs were peripheral neuropathy (19.2%, all were grade 3), lymphopenia (7.7%), elevated glutamyltransferase (7.7%), and hyponatremia (7.7%). Notably, low incidences of liver and renal toxicities, and very limited gastrointestinal toxic effect were observed.

Conclusions

These findings demonstrate that utidelone may be an effective treatment option for advanced NSCLC refractory to second-line treatment.

Clinical trial identification

NCT03693547.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In the randomised BOOSTER trial, primary analysis failed to show superiority of the osimertinib(osi)/bevacizumab(beva) combination versus osi alone. Exploratory analysis found an improvement in progression-free survival (PFS) in current/ever-smokers. The role of smoking status on the benefit of adding an angiogenesis inhibitor to EGFR TKI therapy for EGFR-mutated non-small cell lung cancer (EGFR-NSCLC) patients (pts) remains undetermined.

Methods

A systematic review and meta-analysis was conducted to evaluate the relative effect of adding an angiogenesis inhibitor to EGFR TKI therapy in advanced EGFR-NSCLC pts, according to their smoking status. All relevant randomised studies of osi/erlotinib(erlo) with or without beva/ramucirumab(ramu), appearing in main oncology congresses or in PubMed as of 1^st November 2021, were examined. The hazard ratios (HRs) for the primary endpoint of PFS by smoking status, were used in the analysis. Pooled HRs and the interaction HR, are estimated by fixed or random effect models, depending on the detected degree of heterogeneity.

Results

Seven randomised trials (1,291 pts) were included in the meta-analysis. Five of the studies included pts in 1^st-line (erlo/beva:3; erlo/ramu and osi/beva: 1 each), and two in 2^nd-line (osi/beva). All studies had EGFR-TKI alone as the control arm. For smokers (current or former, n=502), the pooled PFS HR estimate in favour of the combination was statistically significant (HR=0.55; 95% CI: 0.44-0.69; p<0.010) while for non-smokers (n=789), it was not (HR=0.92; 95% CI: 0.66-1.27; p=0.60). Importantly, a significant interaction effect of treatment by smoking was found (HR_interaction =0.62; 95% CI: 0.41-0.93, p=0.020).

Conclusions

In advanced EGFR-NSCLC smoker pts, the addition of an angiogenesis inhibitor (beva, ramu) to EGFR TKI therapy (erlo, osi) was found to provide a statistically significant PFS benefit. Whether this might be due to a specific co-mutational pattern produced by tobacco exposure remains to be determined. The biological basis for this observation should be pursued.

Clinical trial identification

NCT03133546; EudraCT 2016-002029-12.

Legal entity responsible for the study

European Thoracic Oncology Platform (ETOP) c/o IBCSG Effingerstrasse 40 3008 Bern Switzerland.

Funding

AstraZeneca (Study support + Osimertinib) and F. Hoffmann-La Roche (Bevacizumab).

Disclosure

U. Dafni: Financial Interests, Personal, Member, received honorarium: Tumor Agnostic Evidence Generation working Group of Roche. R.A. Soo: Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Lily; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Taiho; Financial Interests, Personal, Advisory Role: Takedo; Financial Interests, Personal, Advisory Role: Yuhan; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Boehringer Ingelheim. S. Peters: Consultation / Advisory role: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Fishawack, Foundation Medicine, Illumina, Imedex, IQVIA, Incyte, Janssen, Medscape, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, OncologyEducation, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, Talk in a company's organized public event: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Illumina, Imedex, Medscape, Merck Sharp & Dohme, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda, Receipt of grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol Myers Squibb; Clovis, GSK, Illumina, Lilly, Merck Sharp & Dohme, Merck Serono, Mirati, Novartis, Pfizer, Phosplatin Therapeutics, Roche/Genentech. J. Han: Financial Interests, Personal, Research Grant: Hoffmann-La Roche Ltd; Financial Interests, Personal, Research Grant: Ono; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: Takeda; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Other, Compensated as an advisor: Medpacto; Financial Interests, Personal, Other, Compensated as an advisor: Abion; Financial Interests, Personal, Other, Compensated as an advisor: Ono; Financial Interests, Personal, Other, Payment or honoraria for lectures,presentations, speakers bureaus, manuscript writing or edu. events: AstraZeneca; Financial Interests, Personal, Other, Payment or honoraria for lectures,presentations, speakers bureaus, manuscript writing or edu. events: Bristol Myers Squibb; Financial Interests, Personal, Other, Payment or honoraria for lectures,presentations, speakers bureaus, manuscript writing or edu. events: F. Hoffmann-La Roche Ltd; Financial Interests, Personal, Other, Payment or honoraria for lectures,presentations, speakers bureaus, manuscript writing or edu. events: Merck Sharpe & Dohme; Financial Interests, Personal, Other, Payment or honoraria for lectures,presentations, speakers bureaus, manuscript writing or edu. events: Takeda; Financial Interests, Personal, Other, Payment or honoraria for lectures,presentations, speakers bureaus, manuscript writing or edu. events: Novartis. J. De Castro: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Other, personal fees: AstraZeneca; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Other, personal fees: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Merck Sharp and Dohme; Financial Interests, Personal, Other, personal fees: Merck Sharp and Dohme; Financial Interests, Personal, Research Grant: Hoffmann-La Roche; Financial Interests, Personal, Other, personal fees: Hoffmann-La Roche; Financial Interests, Personal, Other, personal fees: Bayer; Financial Interests, Personal, Other, personal fees: Boehringer Ingelheim; Financial Interests, Personal, Other, personal fees: GlaxoSmithKlein; Financial Interests, Personal, Other, personal fees: Jansen-Cilag; Financial Interests, Personal, Other, personal fees: Lilly; Financial Interests, Personal, Other, personal fees: Novartis; Financial Interests, Personal, Other, personal fees: Pfizer; Financial Interests, Personal, Other, personal fees: Takdeda. L. Coate: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Daichi. M. Früh: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Other, other support: AstraZeneca; Financial Interests, Personal, Other, other support: Bristol Myers Squibb; Financial Interests, Personal, Other, other support: Boehringer Ingelheim; Financial Interests, Personal, Other, other support: Janssen; Financial Interests, Personal, Other, other support: MSD; Financial Interests, Personal, Other, other support: Pfizer; Financial Interests, Personal, Other, other support: Roche; Financial Interests, Personal, Other, other support: Takeda. E. Nadal: Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Personal fees: Roche; Non-Financial Interests, Personal, Other, non-financial support: Roche; Financial Interests, Personal, Other, personal fees: AstraZeneca; Non-Financial Interests, Personal, Other, non-financial support: AstraZeneca; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Other, personal fees: Bristol Myers Squibb; Non-Financial Interests, Personal, Other, non-financial support: Bristol Myers Squibb; Financial Interests, Personal, Other, personal fees: Merck Sharp Dohme; Non-Financial Interests, Personal, Other, non-financial support: Merck Sharp Dohme; Financial Interests, Personal, Research Grant: Merck Serono; Financial Interests, Personal, Other, personal fees: Merck Serono; Financial Interests, Personal, Other, personal fees: Takeda; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Other, personal fees: Pfizer; Non-Financial Interests, Personal, Other, non-financial support: Pfizer; Financial Interests, Personal, Other, personal fees: Lilly; Financial Interests, Personal, Other, personal fees: Bayer; Financial Interests, Personal, Other, personal fees: Amgen; Financial Interests, Personal, Other, personal fees: Boehringer Ingelheim. E. Carcereny: Financial Interests, Personal, Other, personal fees: AstraZeneca; Financial Interests, Personal, Other, personal fees: Amgen; Financial Interests, Personal, Other, personal fees: Bristol Myers Squibb; Financial Interests, Personal, Other, personal fees: MSD; Financial Interests, Personal, Other, personal fees: Roche. M. Angeles Sala González: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Other, speaker role: Pierre Fabre; Financial Interests, Personal, Other, travel grant: Roche; Financial Interests, Personal, Other, travel grant: PharmaMar. R. Bernabé Caro: Financial Interests, Personal, Other, payment or honoraria for lectures, presentations, speakers’bureaus, manuscript writing or edu. events: Roche; Financial Interests, Personal, Other, payment or honoraria for lectures, presentations, speakers’bureaus, manuscript writing or edu. events: AstraZeneca; Financial Interests, Personal, Other, payment or honoraria for lectures, presentations, speakers’bureaus, manuscript writing or edu. events: Bristol Myers Squibb; Financial Interests, Personal, Other, payment or honoraria for lectures, presentations, speakers’bureaus, manuscript writing or edu. events: Amgen; Financial Interests, Personal, Other, payment or honoraria for lectures, presentations, speakers’bureaus, manuscript writing or edu. events: MSD; Financial Interests, Personal, Other, participation on Data Safety Monitoring Board or Advisory Board: AstraZeneca; Financial Interests, Personal, Other, participation on Data Safety Monitoring Board or Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Other, participation on Data Safety Monitoring Board or Advisory Board: Roche. M. Provencio Pulla: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, personal fees: AstraZeneca; Financial Interests, Personal, Other, personal fees: Bristol Myers Squibb; Financial Interests, Personal, Other, personal fees: Roche; Non-Financial Interests, Personal, Other, non-financial support: AstraZeneca; Non-Financial Interests, Personal, Other, non-financial support: Bristol Myers Squibb; Non-Financial Interests, Personal, Other, non-financial support: Roche; Financial Interests, Personal, Other, personal fees: MSD; Financial Interests, Personal, Other, personal fees: Takeda. S. Cuffe: Non-Financial Interests, Personal, Other, non-financial support: Pfizer; Non-Financial Interests, Personal, Other, non-financial support: Roche; Non-Financial Interests, Personal, Other, non-financial support: MSD; Non-Financial Interests, Personal, Other, non-financial support: Bristol Myers Squibb. R.A. Stahel: Financial Interests, Personal, Advisory Role, consultant or advisory role: AstraZeneca; Financial Interests, Personal, Advisory Role, consultant or advisory role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role, consultant or advisory role: Janssen; Financial Interests, Personal, Advisory Role, consultant or advisory role: MSD; Financial Interests, Personal, Advisory Role, consultant or advisory role: Pfizer; Financial Interests, Personal, Advisory Role, consultant or advisory role: Regeneron; Financial Interests, Personal, Advisory Role, consultant or advisory role: Roche; Financial Interests, Personal, Advisory Role, consultant or advisory role: Seattle Genetics; Financial Interests, Personal, Advisory Role, consultant or advisory role: Takdeda; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Blueprint; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Sandoz; Financial Interests, Personal, Other, DMC role: Genentech/Roche; Financial Interests, Personal, Other, DMC role: Takeda; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: AstraZeneca; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: Bristol Myers Squibb; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: Ipsen; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: MSD; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: Novartis; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: Pierre Fabre; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: Roche; Financial Interests, Personal, Other, financial support for ETOP and IBCSG trials, where he is president and scientific chair: Pfizer. All other authors have declared no conflicts of interest.