Background

In the randomized phase III trial of SABR versus standard radiotherapy for stage I NSCLC (CHISEL TROG09.02), we demonstrated superior progression free and overall survival for patients randomized to SABR. Here we report comparisons in quality of life (QoL) between the two treatment arms.

Methods

Patients with biopsy proven stage I NSCLC confirmed by FDG PET/CT were randomized (2 to 1) to SABR (54 Gy in 3 fractions or 48 Gy in 4 fractions) or standard radiotherapy (66 Gy in 33 fractions or 50 Gy in 20 fractions). The primary endpoint was local progression free survival, with overall survival and QoL secondary endpoints. QoL was measured with the EORTC QLQ C30 and LC13 scales, before treatment, then at 1 and 3 months after treatment, then at 3 monthly intervals until 2 years and then at 6 monthly intervals. The area under the QoL – time curve (AUC) until 3½ years was estimated for each arm and differences between arms calculated using a linear mixed effects model with the appropriate linear contrast applied. Scores were standardised to be on a scale from 0 to 100.

Results

101 patients were randomized, 35 to standard radiotherapy and 66 to SABR. Local failure and overall survival favoured patients randomized to SABR, with hazard ratios of 0.32 (95% CI 0.13, 0.77, P = 0.008) and 0.53 (95% CI 0.30, 0.94, P = 0.027) respectively. For global health status measured with the QLQ C30, the difference in the mean AUC was 5.46 favouring the SABR arm (95% CI -3.6, 14.5). Similarly, there were no significant differences in functional or symptom scales, including fatigue (mean AUC difference 0.83, 95% CI-8.0, 9.7), pain (-3.60, 95% CI -13.4, 6.2) dyspnea (-6.2, 95% CI -16.8, 4.4) or cough (-7.68, 95% CI -19.7, 4.4) - for all these symptom scales, negative values represent lesser symptoms in the SABR arm.

Conclusions

In spite of substantial differences in treatment duration and intensity between the two arms, there were no differences in any of the QoL measures, providing further support for SABR as the standard of care in this patient group.

Clinical trial identification

NCT01014130.

Legal entity responsible for the study

Trans Tasman Radiation Oncology Group.

Funding

The Radiation and Optometry Section of the Australian Government Department of Health with the assistance of Cancer Australia; The Cancer Society of New Zealand; and The Cancer Research Trust, New Zealand.

Disclosure

All authors have declared no conflicts of interest.

Background

Osimertinib, a third-generation, CNS-active EGFR-TKI, potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations. We report results from a second planned interim analysis of the ongoing ASTRIS study (NCT02474355), including analysis of outcomes by specimen source (tissue, plasma or others) used for determining T790M status.

Methods

Pts with T790M-positive advanced NSCLC, assessed by any approved molecular testing method from any specimen, treated with prior EGFR-TKI therapy, with WHO performance status (PS) 0–2 were included. Asymptomatic, stable CNS metastases were permitted. Eligible pts received osimertinib 80 mg once daily. Efficacy outcomes include investigator assessed response, progression-free survival and overall survival.

Results

From 18 Sep 2015 to 20 Oct 2017 data cut-off (DCO), 3014 pts across 16 countries had received ≥1 dose of osimertinib, 2870 had ≥1 investigator-assessed response documented at DCO: median follow-up 7.9 months (range <1–24), median age 62 years (27–92), 13% age ≥75, 64% female, 69% Asian. Samples were assessed for T790M status in tissue (n = 1611, 53%), plasma (n = 1242, 41%) and other specimens (fine needle aspirate, fluid cytology, bone marrow; n = 160, 5%). T790M was tested by cobas® EGFR Mutation Test v2 (n = 1593, 53%), PNA-clamp (n = 371, 12%), Qiagen therascreen (n = 322, 11%) ddPCR (n = 134, 4%). Overall clinical response was reported in 1611/2870 pts (56.1%; 95% CI 54.3, 58.0); 978/1565 pts by tissue (62.5%; 95% CI 60.0, 64.9), 539/1147 pts by plasma (47.0%; 95% CI 44.1, 49.9) and 94/158 pts by other specimens (59.5%; 95% CI 51.4, 67.2). Clinical results in the table.Table: 466O

Efficacy outcomes in FAS and by tissue and plasma T790M test

Conclusions

ASTRIS, the largest real-world study of osimertinib in T790M-positive NSCLC, showed clinical activity consistent with the osimertinib clinical trial program. Clinical outcomes were better in pts T790M positive by tissue compared with pts T790M positive by plasma.

Editorial acknowledgement

Melanie Francis.

Clinical trial identification

NCT02474355.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

H.C. Freitas: Advisory board member: Pfizer, MSD; Steering committee: Astrazeneca; Travel grants: MSD, Pfizer, Roche, Astrazeneca, BMS; Speaker’s bureau: MSD. K. Park: Advisor, consultant: AstraZeneca. M. Tiseo: Advisory boards, speakers’ fee: AstraZeneca J. Laskin: My institution receives funding for studies that I am PI for: Roche, BI, Pfizer, AstraZeneca; Honoraria for academic talks: Roche, AstraZeneca, Pfizer. B. Solomon: Advisory boards, honoraria: AstraZeneca, Roche, Pfizer, Novartis, Merck, Bristol-Myers Squibb. M. Miranda: Permanent employee, shareholder: AstraZeneca. J. Rigas: Employee: Kelly Services as a full-time consultant: AstraZeneca. P.K. Cheema: Advisory board, honoraria: AstraZeneca, Roche, Merck, Bristol-Myers Squibb, Novartis, Takeda, Pfizer. All other authors have declared no conflicts of interest.

Background

Prolonged infusion of low dose gemcitabine (PLDG) in combination with platinum has shown promising activity in terms of improved response rate and progression free survival (PFS); especially in squamous non-small cell lung cancer (NSCLC). In addition PLDG had additional advantage of decreasing the requirement of drug by 75% per dose . Hence, we conducted a phase 3 randomized non-inferiority study with the primary objective of comparing the overall survival (OS) between PLDG and standard dose gemcitabine with platinum in advanced squamous NSCLC.

Methods

Adult subjects (age ≥ 18 years), with stage IIIB-IV, NSCLC, ECOG performance status of ≥ 2 and adequate organ function were randomized 1:1 into either carboplatin (AUC-5 intravenous over 30-60 minutes, Day 1) with standard dose gemcitabine (1000 mg/m2 intravenous over 30 minutes, Day 1 and 8) (STD-G arm) or the same schedule of carboplatin along with low dose gemcitabine (250 mg/m2 intravenous over 6 hours, Day 1 and 8) (LOW-G arm). Planned sample size was 308 for non-inferiority margin for upper limit of hazard ratio 1.33, assuming 80% power and one sided alpha of 0.05. Kaplan Meier method was used for estimation of OS and PFS and compared using log-rank test. A P value of 0.05 was considered as significant.

Results

Out of the 308 patients randomised,155 and 153 patients were randomised in STD-G arm and LOW-G arm, respectively. At the time of data cutoff, 131 and127 patients had died in each arm, respectively. The median overall survival in STG-G arm was 204 days (95%CI 160-255) versus 251 days (95%CI 210-308) in LOW-G arm (P = 0.3). The hazard ratio for death was 0.890 (95%CI 0.697-1.137; P = 0.351). The median progression free survival in STG-G arm was 94 days (95%CI 80-123) versus 119 days (95%CI 92-137) in LOW-G arm (P = 0.658). The hazard ratio for progression was 0.949 (95%CI 0.752-1.197; P = 0.656). There was no statistical difference in adverse event rate between the 2 arms.

Conclusions

This large phase 3 randomised study suggests that PLDG is an alternative to the standard gemcitabine schedule. It produces similar OS and PFS without an increase in adverse event rate.

Clinical trial identification

CTRI/2013/02/003422.

Legal entity responsible for the study

Dr Kumar Prabhash.

Funding

Tata Memorial Hospital.

Disclosure

All authors have declared no conflicts of interest.

Background

In the FLAURA phase 3 study (NCT02296125), the third-generation EGFR-TKI osimertinib significantly improved progression-free survival (PFS) vs SoC EGFR-TKIs (gefitinib or erlotinib) in pts with previously untreated Ex19del/L858R (EGFRm) advanced NSCLC (hazard ratio [HR] 0.46 [95% CI 0.37, 0.57]; p < 0.001). Interim overall survival (OS) data was encouraging but not formally statistically significant (HR 0.63 [95% CI 0.45, 0.88]; p = 0.007). Here we report exploratory post-progression outcomes.

Methods

Pts were randomised 1:1 to receive osimertinib (80 mg orally [PO], once daily [QD]) or SoC (gefitinib 250 mg PO QD or erlotinib 150 mg PO QD). Treatment beyond disease progression was allowed if the investigator judged continued clinical benefit; investigators determined subsequent therapy. Pts receiving SoC could cross over to osimertinib after objective disease progression with documented post-progression T790M-positive mutation status.

Results

At data cutoff, 12 June 2017, 138/279 (49%) and 213/277 (77%) pts discontinued osimertinib and SoC, respectively; 82 (29%) and 129 (47%) received a subsequent treatment: EGFR-TKI-containing, 29 (10%) and 97 (35%; 55 [20%] osimertinib); platinum chemotherapy-containing, 46 (16%) and 27 (10%). Median time (mths) to discontinuation of study treatment or death: osimertinib 20.8 (95% CI 17.2, 24.1) vs SoC 11.5 (10.3, 12.8). Median time (mths) to discontinuation of any EGFR-TKI (study treatment and subsequent EGFR-TKI, not interrupted by non-EGFR-TKI therapy) or death: osimertinib 23.0 (19.5, not calculable [NC]) vs SoC 16.0 (14.8, 18.6). Time-to-event post-progression endpoints all favoured osimertinib (Table).Table: 489O

Conclusions

PFS benefit with osimertinib was preserved throughout time-to-event post-progression endpoints. Step-wise increase of the statistically significant HRs (PFS 0.46, TFST 0.51, PFS2 0.58, TSST 0.60) provides confidence in the interim OS data.

Editorial acknowledgement

Natalie Griffiths.

Clinical trial identification

NCT02296125.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

D. Planchard: Advisory board fees: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Novartis, MSD, Roche, Celgene. M. Boyer: Research grant: AstraZeneca; Personal fees: AstraZeneca, Roche, Merck, Sharp and Dohme, Pfizer, Amgen, Bristol-Myers Squibb. P. Cheema: Advisory board/honorarium: AstraZeneca, Roche, Merck, Bristol-Myers Squibb, Novartis, Takeda, Pfizer. T. Takahashi: Personal fees, grants: AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, MDS K.K. A. Todd: Employee: AstraZeneca. A. McKeown, Y. Rukazenkov: Employee, shareholder: AstraZeneca. Y. Ohe: Grants, personal fees: AstraZeneca, Ono Pharmaceutical, BMS, Chugai, MSD, Novartis, Kyorin, Dainippon-Sumitomo, Daiichi-Sankyo, Boehringer Ingelheim, Bayer, Lilly, Pfizer, Ignyta and Kissei. All other authors have declared no conflicts of interest.

Background

Previous large clinical trials on advanced non-small-cell lung cancer (NSCLC) demonstrated that epidermal growth factor receptor (EGFR)-sensitizing mutations were the most important predictive markers of clinical outcome for EGFR tyrosine kinase inhibitor (TKI) treatment. However, approximately 30% of patients with TKI-sensitizing EGFR mutations do not exhibit objective responses to EGFR TKIs (primary resistance). The mechanism of primary resistance to EGFR tyrosine kinase inhibitors (TKIs) in TKI-sensitizing EGFR-mutant NSCLC has not been clearly understood.

Methods

We screened 3279 patients with NSCLC for EGFR-sensitizing mutations. Among them, 716 patients received icotinib treatment, and a total of 226 patients with stage IIIb-IV EGFR M+ NSCLC were undergoing tumor biopsies or blood withdrawing by the time of primary or acquiring to icotinib, in including formalin-fixed paraffin-embedded (FFPE) samples, serum samples and serous effusions. We used targeted NGS to detect genes status of patients.

Results

Among 226 patients treated with icotinib, 71.7%(162/226) developed acquired resistance, and 28.3%(64/226) had primary resistance. Using the specimens at the baseline, there were 13(20.3%) patients with MET amplication, 8(12.5%) patients with BCL2L11 loss (BIM deletion polymorphism), 8(12.5%) patients with PTEN mutations, 6(9.4%) patients with MTOR mutations, 5(7.8%) patients with PIK3CA mutations, 3(4.7%) patients with FGFR3-TACC3 fusion, 2(3.1%) patients with EGFR T790M mutation, 2(3.1%) patients with HER2 amplication, 1(1.6%) patient with MYC amplication, and 16 (25.0%) patients with unknown status.

Conclusions

MET amplication, BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN, MTOR, PIK3CA mutations), FGFR3-TACC3, T790M, HER2 amplication or MYC amplication might contribute to molecular mechanisms of primary resistance to icotinib in EGFR M+ NSCLC. Further investigations are warranted to overcome these primary resistances.

Legal entity responsible for the study

Qu-Xia Zhang.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Primary results from the global, randomized, double-blind, phase 3 KEYNOTE-407 study (NCT02775435) demonstrated superior OS, PFS, and ORR with pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel (chemo) in patients with previously untreated squamous NSCLC. Here we report results from the East Asia subgroup of KEYNOTE-407.

Methods

In KEYNOTE-407, patients with untreated metastatic squamous NSCLC were randomized 1:1 to carboplatin 6 mg/mL/min and paclitaxel 200 mg/m² Q3W or nab-paclitaxel 100 mg/m² weekly (investigator’s choice) plus pembrolizumab or saline placebo Q3W for 4 cycles followed by pembrolizumab or placebo Q3W for a total of 35 treatment cycles. Randomization was stratified by taxane (paclitaxel vs nab-paclitaxel), PD-L1 (tumor proportion score [TPS] <1% vs ≥ 1%), and region (East Asia vs other). Primary endpoints were OS and PFS (by blinded independent central review [BICR]); ORR by BICR was a secondary endpoint. For the East Asia subgroup, OS and PFS HRs were estimated using an unstratified Cox regression model; between-group difference in ORR was estimated using an unstratified Miettinen & Nurminen method.

Results

Of 559 patients randomized globally, 106 (19.0%) with largely similar baseline characteristics were enrolled from East Asia (pembrolizumab plus chemo, n = 54; placebo plus chemo, n = 52). After median follow-up of 6.7 (range, 0.5–18.9) mo among patients from East-Asia, median (95% CI) OS (16.6 [16.6–NR] mo vs 9.5 [7.5–NR] mo) and PFS (6.3 [5.3–10.2] mo vs 4.1 [3.5–5.2] mo) were longer in those who received pembrolizumab plus chemo vs placebo plus chemo, with HRs of 0.44 [95% CI, 0.22–0.89] and 0.49 [95% CI, 0.30–0.82], respectively. ORR was 63.0% vs 34.6%, respectively (ORR difference, 28.3% [95% CI, 9.3–45.4]). Grade ≥3 AEs occurred in 83.3% of patients in the pembrolizumab plus chemo arm vs 80.8% of those in the placebo plus chemo arm.

Conclusions

Consistent with overall results from KEYNOTE-407, pembrolizumab plus chemo extended OS and PFS, and almost doubled ORR vs placebo plus chemo in patients from East Asia with previously untreated metastatic squamous NSCLC. No new safety signals were observed.

Editorial acknowledgement

Sheri Arndt.

Clinical trial identification

MK-3475-407, NCT02775435.

Legal entity responsible for the study

Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

T. Kato: Grants, personal fees: Abbvie, Astellas, AZ, BI, BMS, Chugai, Eli Lilly, Kyowa Kirin, MSD (inc. for this study), Novartis, Ono, Parexel, Pfizer, Quintiles, Taiho, Roche, Merck Serono, Sumitomo Dainippon. K. Lee: Grants: MSD during the conduct of the study; Personal fees for advisory boards: BMS, MSD outside of the submitted work. R. Hui: Advisory board member: MSD, AstraZeneca, Roche, BMS, Novartis; Speaker honoraria: MSD, Novartis, AstraZeneca, Roche, BMS. B. Balint: No financial interests or arrangements with the sponsor that may bias the results of the study. A. Robinson: Grants: Bristol-Myers Squibb, Merck, Roche, AstraZeneca. I. Okamoto: Grant support: AstraZeneca during conduct of the study. Additional grant support, personal fees (honoraria): AstraZeneca, Ono, BMS, Chugai, Lilly, Taiho, Boehringer Ingelheim and Pfizer outside the submitted work. L. Paz-Ares: Grant and funding to institution for conduct of this study: MSD; Personal fees for advisory boards: MSD, BMS, AstraZeneca, Lilly, Pfizer, Merck-Serono, Roche, Amgen, Takeda, Incyte outside the submitted work. X. Li: Employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Y. Shentu, B. Piperdi: Employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. All other authors have declared no conflicts of interest.

Background

LM are associated with debilitating symptoms and poor prognosis. Osimertinib, a third-generation, CNS-active EGFR-TKI selective for both sensitizing and EGFR T790M resistance mutations, has shown efficacy in pts with CNS metastases; encouraging activity has been reported in pts with LM at 160 mg once daily (QD) (BLOOM; NCT02228369). Here we report LM activity with osimertinib 80 mg QD in pts with LM from four studies across the AURA program (NCT01802632; NCT02094261; NCT02442349; NCT02151981).

Methods

Pts with T790M-positive advanced NSCLC and prior progression on EGFR-TKI therapy received osimertinib 80 mg QD. Asymptomatic, stable CNS metastases, including LM, were allowed. Baseline brain scans were mandated in pts with known or treated CNS metastases at study entry; pts with radiologic evidence of LM by neuroradiological blinded independent review (BICR) were included for analysis. Follow-up brain scans were assessed for radiologic LM response by LM BICR per Response Assessment in Neuro-Oncology LM criteria (Chamberlain et al. Neuro Oncol, 2017, 19:484). Assessment of brain and/or spine imaging was completed qualitatively. Efficacy endpoints included LM objective response rate (ORR), LM duration of response (DoR), LM progression-free survival (PFS) and overall survival (OS). Results are based on the individual data cutoff applied for each study.

Results

Of the 22 pts with LM included for analysis, median treatment exposure was 7.3 months (mo) (range 2.3–16.5). Baseline characteristics were broadly consistent with the overall study population: median age 58 yrs; female 59%; Asian 82%; WHO PS 1 82%. LM ORR was 55% (95% CI 32, 76), with complete LM response and partial LM response reported in 6 pts (27%) each. Median LM DoR for confirmed responders was not calculable (range 1.3–11.1 mo). Median LM PFS was 11.1 mo (95% CI 4.6, NC). Based on available survival data, median OS was 18.8 mo (95% CI 6.3, NC).

Conclusions

Osimertinib showed a clinically meaningful benefit in pts with T790M-positive NSCLC and radiologically detected LM, suggesting 80 mg QD can be an effective dose for management of LM associated with EGFRm NSCLC. Further study is needed to evaluate the role of osimertinib 80 mg QD in pts with LM in a real-world setting.

Editorial acknowledgement

Laura Crocker.

Clinical trial identification

AURA extension (NCT01802632), AURA2 (NCT02094261), AURA3 (NCT02151981), AURA17 (NCT02442349).

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M-J. Ahn: Speakers’ bureau: AstraZeneca, MSD, Ono, Lilly, Roche. C-H. Chiu: Honorarium: AZ, BI, Novartis, Pfizer, Roche. J-Y. Han: Honoraria: Roche; Consulting, advisory role: Novartis, BMS, MSD; Research Funding Roche. S.B. Goldberg: Research support: AstraZeneca; Advisory board member: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb. A. Greystoke: Consultancy fees, speaker fees: AstraZeneca. J. Crawford: Scientific advisor: Amgen, Enzychem, Merck, Pfizer. X. Huang, M. Johnson, K. Vishwanathan: Employee, shareholder; AstraZeneca A. Mendoza-Naranjo: Employee: AstraZeneca T. Mok: ACEA, ASCO, AZ, BI, BMS, Celgene, ChiMed, Cirina, Clovis, CSCO, Eisai, Fishawack, GeneDecode, IASLC, Ignyta, Janssen, Lilly, Merck, MSD, Novartis, Oncogenex, Pfizer, Roche/Genentech, Sanomics, SFJ, Takeda, Taiho, Vertex, XCovery. All other authors have declared no conflicts of interest.

Background

A subset (3%) of NSCLCs harbor MET mutations that cause exon 14 skipping (METex14). We report interim data from a single-arm phase 2 trial of the selective Met inhibitor tepotinib in patients with METex14-skipping mutation-positive (METex14+) NSCLC (NCT02864992).

Methods

Up to 120 adults with advanced Stage IIIB/IV METex14+ NSCLC without EGFR-activating mutations or ALK rearrangements will receive tepotinib 500 mg QD until disease progression, intolerable toxicity or withdrawal. METex14+ mutations were identified in RNA from FPE tumor (T) material and/or plasma (L; 60 patients each, overlap anticipated) by a central laboratory. Primary endpoint: objective response rate (ORR) by independent review. Safety was a secondary endpoint.

Results

To date, 55 patients have been enrolled. Data (based on a cut-off date of 23 March 2018) are available for 38 patients; 28 are evaluable (at least 2 post-baseline assessments or discontinued treatment for any reason) for the primary endpoint (median age 73 [range 39, 89] y; 25 [65.8%] male; 27/9 [71.7%/23.7%] Caucasian/Asian; prior lines of therapy: 0 n = 13; 1 n = 13; 2 n = 11; 3 n = 1). Based on independent review, 12/28 evaluable patients (42.9%) had a confirmed partial response (PR); 6 (21.4%) had stable disease for ≥12 weeks (SD). Based on investigator assessment, 15/28 (53.6%) evaluable patients responded: 2 (7.1%) had a confirmed complete response; 13 (46.4%) had a confirmed PR; 5 (17.9%) had SD. 26 (68.4%) patients had drug-related treatment-emergent adverse events (TEAEs), which were serious in 4 (10.5%) patients (Table). No related TEAEs were grade 4 or led to death. 7 patients have died (4 non-treatment related AEs, 1 progressive disease/disease-related condition, 2 primary cause unknown).

Conclusions

Tepotinib has promising activity in METex14+ NSCLC with a favorable safety profile. Recruitment is ongoing.Table: 493O

Editorial acknowledgement

Lisa Jolly.

Clinical trial identification

NCT02864992.

Legal entity responsible for the study

Merck KGaA.

Funding

Merck KGaA.

Disclosure

H. Sakai: BMS, Ono, MSD, Chugai, Eli Lilly, AstraZeneca E. Felip: Speaker’s bureau, advisory board: AstraZeneca, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Guardant Health, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Abbvie, Merck. A.B. Cortot: Advisory boards: AstraZeneca, Pfizer, Novartis, Roche, MSD, BMS, Takeda, Merck. J. Patel: AbbVie, AstraZeneca, BMS, Takeda advisor; Institutional support: BMS. J. Mazieres: Advisory boards: Roche, BMS, MSD, AstraZeneca, Pfizer, Novartis. R. Bruns: Employment, shares: Merck KGaA. J. Scheele, J. Straub: Employment: Merck KGaA, Darmstadt, Germany. All other authors have declared no conflicts of interest.