Background

The combination of adagrasib (ada), a KRAS^G12C inhibitor, with an immune checkpoint inhibitor (CPI) has demonstrated enhanced preclinical anti-tumor activity. We report safety and efficacy of ada + pembrolizumab (pembro) in patients (pts) enrolled in the KRYSTAL-1 (NCT03785249) and KRYSTAL-7 (NCT04613596) trials.

Methods

In a Ph 1b cohort of KRYSTAL-1 and Ph 2 KRYSTAL-7, pts with treatment-naïve, KRAS^G12C-mutated, advanced NSCLC received concurrent ada 400 mg BID + pembro 200 mg Q3W. Pts were enrolled across all PD-L1 levels. Endpoints were safety and efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]).

Results

As of 30 Aug 2022, 75 pts (median follow-up 3.5 mo) had received ada + pembro in KRYSTAL-7 and were safety evaluable. Median age was 66 yrs, 51% were female, 35%/65% were ECOG PS 0/1. Any grade treatment-related adverse events (TRAEs) occurred in 83% of pts; most common were nausea (48%), diarrhea (43%) and vomiting (24%). Grade 3–4 TRAEs occurred in 44% of pts; most common were increased lipase (11%) and increased ALT/AST (8%/9%), all Grade 3. There were no Grade 5 TRAEs. TRAEs led to both ada and pembro discontinuation in 3% of pts. In a preliminary analysis of tumor response among 53 pts with at least 1 on-study scan (median treatment duration 2 mo), ORR was 49% (26/53 [5 uPR]) and disease control rate (DCR) was 89%; 6 pts had responses on the second on-study scan or later and ORR was 56% in pts enrolled ≥6 mo before data cut-off. DOR, PFS, and OS were not mature, with most pts still on treatment. In KRYSTAL-1, 7 pts (median follow-up 19.3 mo) were clinically evaluable. ORR was 57% (4/7), DCR was 100%; treatment was ongoing >18 months in 2 responders. Safety was consistent with KRYSTAL-7. Additional analyses will be presented.

Conclusions

In the largest dataset evaluating a KRAS^G12C inhibitor combined with a CPI as first-line treatment for NSCLC presented to date, concurrent ada 400 mg BID in combination with pembro had manageable toxicity and demonstrated encouraging preliminary efficacy.

Clinical trial identification

NCT03785249, NCT04613596.

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Victoria Eyre-Brook, PhD, and Charlotte Kennerley, PhD, of Ashfield MedComms, an Inizio company, and funded by Mirati Therapeutics, Inc.

Legal entity responsible for the study

Mirati Therapeutics, Inc.

Funding

Mirati Therapeutics, Inc.

Disclosure

P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, Allorion Therapeutics, Accutar Biotech, Abbvie; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, BMS, Eli Lilly, Takeda, Sanofi, Janssen; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Seranno; Financial Interests, Institutional, Invited Speaker: Pfizer, Gilead, AZ, Genmab. F. de Marinis: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, Bristol Myers Squibb, Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Bristol Myers Squibb, Novartis. J. Laskin: Financial Interests, Personal, Invited Speaker: Roche Canada, Jazz Pharma, AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer, Eli Lilly; Financial Interests, Institutional, Research Grant: Roche Canada. M. Domine Gomez: Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche; Financial Interests, Personal, Principal Investigator: Amgen, AstraZeneca, BeiGene, Daichi, Gilead, Janssen, Mirati, MSD, Takeda. S. Gadgeel: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, Genentech/Roche, Bristol Myers Squibb, Pfizer, Novartis, Blueprint, Daichii, Mirati, Lilly, Merck, Esai, Blueprint, GSK; Financial Interests, Personal, Other, Data Safety Monitoring Board: AstraZeneca. M.C. Garassino: Financial Interests, Personal, Advisory Board: Eli Lilly, SeaGen International GmbH, Eli Lilly, Daiichi Sankyo, Incyte, GlaxoSmithKline, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, AstraZeneca and Daiichi Sankyo Oncology Teams, Roche, Daiichi Sankyo, Mirati Therapeutics, Inc, Daiichi Sankyo/AstraZeneca, AstraZeneca Poland, Daiichi Sankyo, Inc., MSD, Eli Lilly, Pfizer, Astrazenca/MedImmune, Sanofi Genzyme corporation, Sanofi / Prex, Regeneron Pharmaceuticals, Eli Lilly, Mirati Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker: WebMD, WebMD Oncology/Takeda, MSD, MSD Italia, Srl, GrupoPacifico-Secretaria Técnica ICAPEM/AstraZeneca, S.O.S S.r.l, Medscape, ecancer; Financial Interests, Personal, Invited Speaker, Global Experts Meeting: AstraZeneca; Financial Interests, Personal, Other, AstraZeneca Spain: Invitation to a lung cancer investigator meeting: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Board Nazionale Brigatinib: Takeda; Financial Interests, Personal, Other, PACIFIC-R Global Scientific Committee: AstraZeneca; Financial Interests, Personal, Other, Steering Committee member and Co-chair at the AstraZeneca Lung Cancer Summit 2019: AstraZeneca; Financial Interests, Personal, Other, MK-3475 KN671 Steering Committee: MSD; Financial Interests, Personal, Other, Pacific 6 International Coordinating Investigator: AstraZeneca; Financial Interests, Personal, Other, Jannesen Scientific Advisory Board and Therapeutic Area Steering Committee Meeting on Lung Cancer: Janssen; Financial Interests, Personal, Expert Testimony: AstraZeneca UK; Financial Interests, Personal, Other, Pfizer Global Lung Cancer Educational Programme - Steering Committee: Pfizer; Financial Interests, Personal, Other, Seattle Genetics Lung Cancer Platform Study: Seattle Genetics; Financial Interests, Personal, Other, GSK Lung Cancer Global Council: GSK; Financial Interests, Personal, Other, PACIFIC-R Scientific Committee: AstraZeneca UK; Financial Interests, Personal, Other, GSK-Garassino- ZEAL Steering Committee 2020-23: GSK; Financial Interests, Personal, Invited Speaker, Member of the MK-3475 KN671 Steering Committee (KEYNOTE-671): MSD; Financial Interests, Personal, Invited Speaker, Coordinating investigator for the MK-3475 KEYNOTE 189: MSD; Financial Interests, Personal and Institutional, Invited Speaker, Pacific 6 Steering Committee and International Coordinating Investigator: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Steering Committee ML41118 Roche: Roche; Financial Interests, Institutional, Invited Speaker, TURNING POINT: Bayer; Financial Interests, Institutional, Invited Speaker, A Phase 1: Janssen; Financial Interests, Institutional, Invited Speaker, Array 818-202: Pfizer; Financial Interests, Institutional, Invited Speaker, PAPILLON Study: Janssen; Financial Interests, Institutional, Invited Speaker, Phase II: Celgene Corporation, Spectrum Pharmaceuticals, Merk Serono; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker, Phase 3: Bluprint; Financial Interests, Institutional, Invited Speaker, Phase III: Amgen, GlaxoSmithkline Research & Develpoment Ltd., Novartis; Financial Interests, Institutional, Invited Speaker, Phase III - CEACAM5: Sanofi; Financial Interests, Institutional, Invited Speaker, Phase I-JNJ-61186372, a Human Bispecific EGFR and cMet Antibody: Janssen; Financial Interests, Institutional, Invited Speaker, Phase 3 Study RESILIENT: IPSEN Bioscience Inc.; Financial Interests, Institutional, Invited Speaker, Phase II - SAVANNAH: AstraZeneca S.p.A.; Financial Interests, Institutional, Invited Speaker, phase III NEOCOAST: MedImmune Lcc; Financial Interests, Institutional, Invited Speaker, Phase II - coast: MedImmune LCC; Financial Interests, Institutional, Invited Speaker, Phase III - ADRIATIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Phase III (CANOPY-1): Novartis; Financial Interests, Institutional, Invited Speaker, Phase 1b: Exelixis Inc.; Financial Interests, Institutional, Invited Speaker, Phase 3-GO40241: Roche; Financial Interests, Institutional, Invited Speaker, Phase III- CASPIAN: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MK3475-091 - PEARLS: Merk; Financial Interests, Institutional, Invited Speaker, Phase III - ROCHE GO29431: Roche; Financial Interests, Institutional, Invited Speaker, Phase III CA209-017: BMS; Financial Interests, Institutional, Invited Speaker, Phase III - ARCTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Phase III - AURA 3: AstraZeneca AB; Financial Interests, Institutional, Invited Speaker, Phase III CA209-057: BMS; Financial Interests, Institutional, Invited Speaker, OPEL/2014/14/067: Otsuka Pharmaceutical Italy S.r.l.; Financial Interests, Institutional, Invited Speaker, Phase II - VISION: Merck KGaA; Financial Interests, Institutional, Invited Speaker, Phase III MK-3475-715: Incyte Corporation; Financial Interests, Institutional, Invited Speaker, Phase 1/2 (TRIDENT-1): Turning Point Therapeutics, Inc.; Financial Interests, Institutional, Invited Speaker, HERTHENA-Lung01: A Phase 2: Daiichi Sankyo Development Ltd.; Financial Interests, Institutional, Invited Speaker, Phase II ATLANTIC: AstraZeneca S.p.A.; Non-Financial Interests, Personal, Principal Investigator, STYLE Trial: Pfizer; Non-Financial Interests, Personal, Principal Investigator, Studio TYME: Eli Lilly; Non-Financial Interests, Personal, Principal Investigator, People: MSD; Non-Financial Interests, Personal, Principal Investigator, FAME trial: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, POST-ALK: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, Bando finalizzata Mesotelioma: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, TERAVOLT: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, Progetto Timoma: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, APOLLO: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, Beverly: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Personal, Principal Investigator, IND227: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Personal, Principal Investigator, RAMES: GOIRC; Non-Financial Interests, Personal, Principal Investigator, Studio CHANCE: GOIRC; Non-Financial Interests, Personal, Principal Investigator, Creta trial: Sant'Orsola Malpighi - Bologna (Alma Mater Studiorum Università Bologna); Non-Financial Interests, Personal, Principal Investigator, MILES 5: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Personal, Leadership Role, President and Founder: Women for Oncology Italy; Non-Financial Interests, Personal, Principal Investigator, LIPI: GUSTAVE-ROUSSY PARIGI LIPI TRIAL- no profit; Non-Financial Interests, Personal, Principal Investigator: AO Spedali Civili Brescia; Non-Financial Interests, Personal, Principal Investigator, phase III trial: European Thoracic Oncology Platform (ETOP); Non-Financial Interests, Personal, Other, Member of ASCO Scientific Committee (2018-2021): ASCO; Non-Financial Interests, Personal, Leadership Role, Board member: AIOT (Associazione Italiana Oncologia Toracica); Non-Financial Interests, Personal, Member: AIOM, AIOT; Non-Financial Interests, Personal, Member, WCLC annual congress Lung Cancer Track: WCLC; Non-Financial Interests, Personal, Member, Scientific Committee: IPOP (Italian lung cancer charity), TUTOR (Italian thymic malignancies charity); Non-Financial Interests, Personal, Member, Member since 2013: EMA Scientific Advisory Group (SAG); Non-Financial Interests, Personal, Other, Scientific Programme Committee: AACR; Non-Financial Interests, Personal, Leadership Role, ESMO National Societies Committee Chair and ESMO Council Member: ESMO; Other, Personal, Other, Travel, Accommodations, Expenses: Pfizer; Other, Personal, Other, Relationships to Disclose Travel, Accommodations, Expenses: Roche, AstraZeneca. S. Lu: Financial Interests, Institutional, Invited Speaker: Hansoh, AstraZeneca, Roche; Financial Interests, Personal, Research Grant: AstraZeneca, Hutchison, BMS, Heng Rui Beigene, Roche, Hansoh. A.S. Spira: Financial Interests, Personal, Invited Speaker: Mirati. V. Kang: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc. S. Roshan: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc. X. Yan: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: Mirati Therapeutics, Inc. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Merck Sharp & Dohme, Pfizer, Sanofi, Takeda, Merck Serono, Peptomyc, F. Hoffmann-La Roche, Novartis, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono, Sanofi, Takeda, TouchOncology; Financial Interests, Institutional, Other, Grant for oncology innovation: Merck Healthcare KGAa; Financial Interests, Institutional, Other, Fundación Merck Salud: Fundación Merck Salud; Financial Interests, Personal, Invited Speaker, Independent member: Grifols; Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GlaxoSmithKline Research & Development Limited, Abbvie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol-Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc; Non-Financial Interests, Personal, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Personal, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO; Non-Financial Interests, Personal, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform).

Background

Consolidation immunotherapy (IO) after chemoradiation is the standard of care for stage III uNSCLC. Addition of IO-based induction therapy may further improve outcome, partly by enabling surgery. SHR-1701 is a novel anti-PD-L1/TGFβRII fusion protein. We assessed neoadjuvant SHR-1701 ± chemo, followed by surgery or RT in untreated stage III uNSCLC without EGFR/ALK alterations.

Methods

Pts were given 3 cycles of neoadjuvant SHR-1701 (30 mg/kg Q3W) ± chemo (paclitaxel 175 mg/m² Q3W + carboplatin AUC=5 Q3W). Pts with PD-L1 TPS <50% received combo-therapy (arm A) and those with PD-L1 TPS ≥50% were randomized (1:1) to receive combo-therapy (arm B) or SHR-1701 alone (arm C). After assessment by MDT, pts received surgery or definitive RT (60 Gy/30 fractions) + concurrent cisplatin (30 mg/m² QW), followed by SHR-1701 for 16 cycles. The primary endpoints were post-induction ORR and event-free survival (EFS).

Results

107 pts were enrolled (arm A/B/C, n=88/9/10; median age, 59 y; squamous NSCLC, 76.6%; stage IIIA/B/C, 25.2%/43.9%/29.9%). In all pts, the post-induction and best overall ORR were 56.1% (95% CI 46.2-65.7) and 70.1% (60.5-78.6). mEFS was 18.2 mo (95% CI 11.8-not reached [NR]). Efficacy by study arm is shown in Table 1. 27 (25.2% of 107; baseline stage IIIA/B/C, 37.0%/44.4%/18.5%) pts underwent surgery (lobectomy/bilobectomy/pneumonectomy, 88.9%/7.4%/3.7%); all achieved R0 resection. Among them, 12 (44.4%) MPR and 7 (25.9%) pCR were recorded. Nodal downstaging was seen in 14 pts (51.9%; pN2 to pN0/1, 8/14 [57.1%]; pN3 to pN0-2, 6/9 [66.7%]). mEFS was NR in resected pts. Grade ≥3 TRAEs occurred in 77 (72.0%) pts; all with frequency ≥10% were hematotoxicities. No new safety signals were identified. Table: LBA5

Efficacy by study arm

Conclusions

SHR-1701 ± chemo showed promising antitumor activity with a tolerable safety profile in stage III uNSCLC. Some pts could switch from unresectable to resectable and get much better efficacy. Phase 3 investigation is warranted.

Clinical trial identification

NCT04580498.

Legal entity responsible for the study

Jiangsu Hengrui Pharmaceuticals, Co., Ltd.

Funding

Jiangsu Hengrui Pharmaceuticals, Co., Ltd.

Disclosure

Y. Wu: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol Myers Squibb, Hengrui; Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Boehringer Ingelheim, Takeda; Financial Interests, Personal, Research Grant: Boehringer Ingelheim, Roche, Pfizer, Bristol Myers Squibb. J. Shuang, L. Song, W. Shi: Financial Interests, Personal, Full or part-time Employment: Hengrui. All other authors have declared no conflicts of interest.

Background

Resectable NSCLC with neoadjuvant chemotherapy(CT) has favourable outcomes. However, with few neoadjuvant immunotherapy trials, detailed information on patients(pts) with resectable stage IIIA and IIIB(T3N2) NSCLC is available. Camrelizumab(Cam), a PD-1 antibody, has shown a survival benefit in patients with advanced NSCLC. However, the antitumor activity and safety of Cam plus CT in the neoadjuvant setting is unknown. Here, we report the final analysis from this multi-center, open-label, randomized controlled phase II trial.

Methods

Stage IIIA or IIIB(T3N2) resectable NSCLC were randomized (1:1) to receive Cam, albumin-bound paclitaxel (ab-Pac) and platinum, or ab-Pac plus platinum of a 21-day cycle for 3 cycles(n=47 each). Definitive surgery was to be performed within 4∼6 weeks of treatment. The primary endpoint was pCR. Secondary endpoints included MPR, ORR, DFS by RECIST 1.1, and safety.

Results

From 3/2020 to 9/2022, 94 pts were enrolled and randomly assigned (n=47 each), and 88 pts received neoadjuvant treatment (43 in Cam+CT and 45 in CT). The patient characteristics of both arms were well balanced in the full analysis(FAS). In Cam+CT, 42 pts completed neoadjuvant therapy and efficacy evaluation, among of which 40 had underwent surgery, and in CT, 45 pts completed neoadjuvant therapy and efficacy evaluation, of which 42 underwent surgery. Neoadjuvant Cam+CT significantly increased the pCR rate compared to chemo in the FAS (32.56% vs 8.89%, P =0.0079). Cam+CT also improved MPR rates vs chemo in the FAS (15.56% vs 65.12%), as well as ORR (53.33% vs 72.09%), and 1-year DFS achieved 93.243% and 81.377% respectively. Adverse events (AEs) of the two arms were similar, except reactive cutaneous capillary endothelial proliferation (44.19%; grade 1-2) in the Cam+CT arm. No AEs beyond expectation or of grade 3-5 were reported.

Conclusions

This updated analysis confirms the superiority of the chemo-immuno combination in patients with resectable stage IIIA or IIIB(T3N2) NSCLC in terms of pCR, with a moderate increase in grade 3-5 toxicity. Thus, this treatment should become the standard of care in these patients.

Clinical trial identification

NCT04338620.

Legal entity responsible for the study

The authors.

Funding

Jiangsu Hengrui Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

Background

IMpower010 (NCT02486718) showed that adjuvant atezo improved disease-free survival (DFS) vs BSC in pts with PD-L1 tumour cell (TC) ≥1% stage II-IIIA NSCLC. While a ctDNA positive (+) status post-surgery (Post-OP ctDNA) conferred poor prognosis, atezo was beneficial vs BSC irrespective of Post-OP ctDNA status (Zhou ESMO-IO 2021). The current exploratory analysis evaluated (1) association of atezo clinical outcomes by PD-L1 status and Post-OP ctDNA status and (2) association of ctDNA clearance post-chemo and pre-atezo cycle 1 day 1 (Post-chemo ctDNA), as well as post-atezo/BSC treatment (on-treatment), with DFS by arm in atezo and BSC pts.

Methods

Of 1005 randomized pts, 600 were evaluated for Post-OP ctDNA using the Signatera (Natera) RUO test. 118 of 600 pts were Post-OP ctDNA+. Of these, 103 pts were evaluated for ctDNA Post-chemo ctDNA and on-treatment at Wk 6 (C3; n=94), Wk 12 (C5; n=85), Wk 18 or 21 (C7/8; n=73) and Wk 42 or 45 (C15/16; n=46). PD-L1 TC subgroups <1%, ≥1%, 1-49% and ≥50% were determined using the VENTANA SP263 assay.

Results

Regardless of Post-OP ctDNA status, atezo was associated with improved DFS vs BSC in PD-L1+ subgroups (TC ≥1%, 1-49%, ≥50%) but not the PD-L1− subgroup (TC <1%). 62.1% (64/103) of Post-OP ctDNA+ pts were cleared (ctDNA−) at Post-chemo ctDNA, which was linked to improved DFS. Atezo improved DFS vs BSC regardless of ctDNA clearance at Post-chemo ctDNA (Cleared: DFS, 31.3 (atezo) vs 13.3 mo (BSC); HR [95% CI], 0.7 [0.37, 1.34] vs Not cleared: DFS, 4.2 vs 3.9 mo; 0.67 [0.34, 1.32]). Longitudinal assessment of ctDNA+ pts at Post-chemo ctDNA showed that atezo maintained ctDNA levels over time, while an approximate 10× increase was observed with BSC. The median time to convert to ctDNA+ in pts who were ctDNA− at Post-chemo ctDNA was longer with atezo vs BSC (not reached vs 4.67 mo; HR, 0.60 [95% CI: 0.31, 1.17]). Similarly, improved DFS was seen with atezo vs BSC in these pts (31.3 vs 13.3 mo; HR, 0.7 [95% CI: 0.37, 1.34]).

Conclusions

Adjuvant atezo is linked to improved DFS vs BSC in early NSCLC in PD-L1+ subgroups regardless of ctDNA status. Chemo ctDNA clearance is associated with longer DFS and atezo may control ctDNA levels and delay disease recurrence better than BSC.

Clinical trial identification

NCT02486718.

Editorial acknowledgement

Medical writing support for this abstract was provided by Michael Williams, PhD, of Health Interactions, Inc. and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffman-La Roche, Ltd.

Disclosure

E. Felip: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Roche, Janssen, Merck Sharp & Dohme, Merck Serono, Pfizer, PeerVoice, Springer, Touch Medical; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Roche, GlaxoSmithKline, Medical Trends, Peptomyc, Puma Biotechnology, Regeneron, Sanofi, Takeda; Other, Institutional, Research Grant, Research Grant: Oncology Innovation, Merck Healthcare KGAa, Fundacion Merck Salud; Other, Personal, Member of the Board of Directors, Independent Member of the Board: GRIFOLS. M. Srivastava: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. M. Reck: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Merck, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Mirati, Pfizer, Sanofi, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche. H. Wakelee: Financial Interests, Institutional, Research Grant, Research Funding: ACEA Biosciences, Arrys Therapeutics, AstraZeneca/MedImmune, BMS, Celgene, Clovis Oncology, Genentech/Roche, Merck, Novartis, Pharmacyclics, Seagen, Xcovery, Helsinn; Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Daiichi Sankyo, Blueprint, Mirati; Non-Financial Interests, Personal, Advisory Board: Merck, Genentech/Roche; Other, Personal, Leadership Role, President: IASLC; Other, Personal, Leadership Role, Executive Committee: ECOG-ACRIN. N.K. Altorki: Financial Interests, Institutional, Research Grant, PI: AstraZeneca, Janssen; Financial Interests, Personal, Other, Steering Committee Member: Roche. E. Vallieres: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Oncocyte; Financial Interests, Personal, Advisory Board: BMS. H. Tanaka: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharmaceutical, AstraZeneca, Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Ono Pharmaceutical. S. McCune: Financial Interests, Institutional, Other, Support from Genentech as a research site for this trial: Genentech. E. Bennett, B.J. Gitlitz, V.A. McNally: Financial Interests, Personal, Full or part-time Employment: Roche; Financial Interests, Personal, Stocks/Shares: Roche. S. Novello: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Speaker’s Bureau: AMG, Roche, Takeda, Pfizer, AZ, Thermofisher, Novartis, Sanofi, BeiGene; Financial Interests, Personal, Advisory Role, Advisor: AMG, Roche, Takeda, Pfizer, AZ, Novartis, Sanofi, BeiGene. M. Ballinger: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. W. Zou, B. Nabet, M. Das Thakur: Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Roche. C. Zhou: Financial Interests, Personal, Invited Speaker: Roche China, Lily China, Boehringer Ingelheim, Sanofi, C-Stone, Qilu, Hengrui, Innovent Biologics, LUYE Pharma, TopAlliance Bioscience Inc, Amoy Diagnostics. All other authors have declared no conflicts of interest.

Background

Following the PACIFIC trial, consolidation D for up to 12 months became a global SoC for pts with unresectable Stage III NSCLC and no disease progression after platinum-based CRT. We report the first planned analysis of OS from PACIFIC-R (NCT03798535), an international study assessing the effectiveness of D in pts from an early access programme (EAP).

Methods

PACIFIC-R is an observational, retrospective study of a cohort of pts with unresectable Stage III NSCLC who received ≥1 dose of D (10 mg/kg IV Q2W) within an AstraZeneca-initiated EAP between September 2017 and December 2018. The primary endpoints are investigator-assessed real-world progression-free survival (rwPFS; reported previously) and OS, assessed by Kaplan–Meier method.

Results

As of 30 November 2021, the full analysis set included 1154 pts from 10 countries. The median (range) follow-up duration in pts censored at the end of data extraction was 38.7 (13.6–49.0) months. Overall, 446 (38.6%) pts had died; median OS (95% CI) was not reached (46.3 months–not estimable) and 2- and 3-year OS rates (95% CI) were 72.3% (69.7–74.8) and 63.2% (60.3–65.9), respectively. OS rates were numerically higher in pts who received concurrent vs sequential CRT, pts with programmed cell death-ligand 1 (PD-L1) expression ≥1% vs <1%, and pts who started D ≤42 vs >42 days after finishing RT (Table). In total, 666 (57.7%) pts had progression events; updated median rwPFS (95% CI) was 24.1 months (20.2–27.8) and 2- and 3-year rwPFS rates (95% CI) were 50.1% (47.2–53.0) and 42.2% (39.2–45.1), respectively. Table: 58O

Conclusions

PACIFIC-R data continue to provide evidence for the effectiveness of consolidation D after CRT in a large, diverse, real-world population, consistent with the PACIFIC trial. Favourable OS results were observed across subgroups, including pts who received sequential CRT and pts with PD-L1 <1%, with consistent rwPFS outcomes.

Clinical trial identification

NCT03798535.

Editorial acknowledgement

Medical writing support, under the direction of the authors, was provided by Aaron Korpal, PhD, of Ashfield MedComms (Manchester, UK), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, MSD, Roche, Pfizer, Mirati, Amgen, Novartis, Sanofi; Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, MSD, Roche, Pfizer, Janssen, Boehringer, Novartis, Sanofi, AbbVie, Amgen, Lilly, Grunenthal, Takeda, Owkin; Financial Interests, Institutional, Research Grant, Local: Roche, Sivan, Janssen; Financial Interests, Institutional, Funding: BMS; Non-Financial Interests, Personal, Officer, International Thymic malignancy interest group, president: ITMIG; Other, Personal, Other, Family member is an employee: AstraZeneca. D.C.C. Christoph: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, Bristol Myers Squibb, Merck Sharp & Dohme, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen, Amgen; Financial Interests, Personal, Funding: AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, Bristol Myers Squibb, Merck Sharp & Dohme, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen, Amgen; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, Bristol Myers Squibb, Merck Sharp & Dohme, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen, Amgen. M.C. Garassino: Financial Interests, Personal, Other: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regerenon, Merck; Financial Interests, Institutional, Other: Eli Lilly, MSD, Pfizer (MISP); AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, Glaxo Smith Kline GSK, Spectrum pharm; Other, Personal and Institutional, Other: AIRC, AIFA, Italian Moh, TRANSCAN, research fundings. F. McDonald: Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Boehringer Ingelheim; Financial Interests, Personal and Institutional, Advisory Board: Boehringer Ingelheim. J.K. Field: Financial Interests, Personal, Advisory Board: Epigenomics, NUCLLEIX Ltd., AstraZeneca, iDNA, Qure.ai; Financial Interests, Personal, Research Grant: Janssen Research & Development, Llc. R. Fietkau: Financial Interests, Personal and Institutional, Advisory Board: Merck Darmstadt, AstraZeneca, MSD; Financial Interests, Personal and Institutional, Funding: Merck Darmstadt, AstraZeneca, MSD, Siemans/Varian; Financial Interests, Personal and Institutional, Other, Honoraria: Merck Darmstadt, AstraZeneca, MSD, Sennewald, Siemens/Varian; Financial Interests, Personal and Institutional, Invited Speaker: Merck Darmstadt, AstraZeneca, Siemens/Varian; Financial Interests, Personal and Institutional, Advisory Role: MSD. P. Garrido Lopez: Financial Interests, Personal and Institutional, Advisory Board: AbbVie, Amgen, Bayer, AstraZeneca, BMS, GSK, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal and Institutional, Principal Investigator: Amgen, Bayer, AstraZeneca, BMS, GSK, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda, Medscape, TouchTime; Financial Interests, Personal and Institutional, Other, Travel/Accommodation/Expenses: AstraZeneca, BMS; Financial Interests, Personal and Institutional, Speaker’s Bureau: BMS; Financial Interests, Personal and Institutional, Training: Janssen; Financial Interests, Personal and Institutional, Full or part-time Employment: Teva. V.D. Haakensen: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS; Financial Interests, Personal, Other, Honoraria: AstraZeneca, BMS, Takeda, Pfizer. S. Siva: Other, Institutional, Research Grant: Bayer Pharmaceuticals, Varian Industries; Financial Interests, Personal, Invited Speaker: AstraZeneca. M. van den Heuvel: Financial Interests, Personal, Advisory Board: AZD; Financial Interests, Personal, Invited Speaker: AZD; Financial Interests, Personal, Research Grant: AZD. J. Bar: Financial Interests, Personal, Advisory Board: AbbVie, MSD, Roche, Takeda, AstraZeneca, Amgen, BMS, Novartis; Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Principal Investigator: AbbVie; Financial Interests, Personal, Research Grant: AbbVie; Non-Financial Interests, Personal, Principal Investigator: MSD, Roche, Takeda, AstraZeneca. C. Chouaid: Financial Interests, Personal, Advisory Board: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen; Financial Interests, Personal, Funding: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen; Financial Interests, Personal, Other, Honoraria: AZ, BI, GSK, Roche, Sanofi Aventis, BMS, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, Janssen and Amgen. P. Vercauter: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Bayer, Bristol Meyers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Roche; Financial Interests, Personal, Research Grant: Chiesi. P. Chander: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. M. Licour: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. S. Anand: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. A.R.M.D. de Lima: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. A.R.R. Filippi: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca, Roche; Financial Interests, Personal, Funding: AstraZeneca, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Principal Investigator: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Roche, Ipsen. All other authors have declared no conflicts of interest.

Background

PD-(L)1 inhibitors have a prominent role in the treatment (tx) of NSCLC, with pembro a commonly used agent, but with no direct comparisons between inhibitors to date. This global, randomized, Phase II double-blind study (PERLA; NCT04581824) compared the efficacy and safety of dostar + CT versus pembro + CT in patients (pts) with first-line (1L) metastatic non-squamous NSCLC.

Methods

Pts with no known EGFR, ALK or other genomic aberrations actionable locally by targeted therapies, known PD-L1 status, ECOG PS 0–1, and no prior systemic tx for metastatic NSCLC were randomized 1:1 to dostar 500 mg or pembro 200 mg Q3W IV ≤35 cycles, both in combination with CT (4 cycles pemetrexed [pem; 500 mg/m²] + carboplatin [AUC 5 mg/mL/min] or cisplatin [75 mg/m²] then pem up to cycle 35) Q3W IV. Primary endpoint was ORR by BICR (RECIST V1.1; difference by Mantel and Haenszel test and Sato’s variance estimator; point estimates by Clopper-Pearson). Safety was a secondary endpoint. Disease assessments were at wks 6 & 12, then every 9 wks x4, then every 12 wks.

Results

121 and 122 pts in the dostar + CT and pembro + CT arms were treated and evaluable, respectively; 41% and 42% had PD-L1 TPS <1; 36% had TPS 1–49% and 22% had TPS ≥50 in both arms. ORR was 46% for dostar + CT, with 2 complete responses [CRs] (2%) and 54 partial responses [PRs] (45%); ORR was 37% for pembro + CT, with 3 CRs (2%) and 42 PRs (34%) (9.3% difference [95% CI: −2.7–21.3]). Safety is shown in the table. Additional analyses (inc. PFS [secondary endpoint], PD-L1 sub-analyses and DOR [exploratory]) will be presented. Table: 57O

Conclusions

In this first randomized phase II study to directly compare PD-1 inhibitors, dostar + CT showed comparable efficacy to pembro + CT in 1L metastatic non-squamous non-oncogenic NSCLC. Safety profiles were similar and consistent with published data.

Clinical trial identification

NCT04581824.

Editorial acknowledgement

Dr. Peters and Dr. Lim are co-primary authors. Editorial support from Fishawack Health, funded by GSK.

Legal entity responsible for the study

GSK.

Funding

GSK (213403).

Disclosure

S. Peters: Financial Interests, Personal, Advisory Role: AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, Beigene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Gilead, GSK, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Ro; Financial Interests, Personal, Invited Speaker: AiCME, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati, Novartis, PER, Peerview, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Beigene, Bristol-Myers Squibb, GSK, Merck Sharp and Dohme, Roche/Genentech. S.M. Lim: Financial Interests, Personal, Research Grant: Yuhan, Janssen; Financial Interests, Personal, Other, Consulting: AstraZeneca, Boehringer Ingelheim, Lilly, Takeda, J Ints Bio; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, GSK, Roche, Hengrui, BridgeBio Therapeutics, Oscotec, Daichii-Sankyo. A.L.O. Ortega Granados: Financial Interests, Personal and Institutional, Full or part-time Employment: Servicio Andaluz de Salud; Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Merck Sharp Dohme. C.S. Fuentes: Financial Interests, Personal, Invited Speaker: Fundacion Respirar. G. Lo Russo: Financial Interests, Personal, Other, Consulting: Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, Amgen , Sanofi, Italfarmaco, Pfizer; Financial Interests, Personal, Other, Honoraria: Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, Amgen, Sanofi ; Financial Interests, Personal, Other, Travel: Roche, BMS, MSD ; Financial Interests, Personal, Advisory Role: Roche, Novartis, BMS, MSD, AstraZeneca, Sanofi ; Financial Interests, Personal, Other, PI in sponsored clinical trials: Roche, Novartis, BMS, MSD, AstraZeneca, GSK, Amgen, Sanofi . M. Schenker: Financial Interests, Personal and Institutional, Invited Speaker, Payment for Clinical trials activities: B.M.S., M.S.D., Roche, Merck Serono, Sanofi, Regeneron, AstraZeneca, Pfizer, G.S.K, Novartis, Astellas, Pharma Mar, BeiGene, Clovis Pharmaceutical, AbbVie, Bioven, Mylan, Samsung Pharmaceutical, Eisai, Gilead, Amgen, Daiichi Sankyo. J.S. Ahn: Financial Interests, Personal, Invited Speaker: Amgen Korea, Yuhan, AstraZeneca Korea, Menarini Korea, Bayer Korea, Takeda Phar, Novartis Korea, Hanmi, BC World, Pfizer, Roche Korea, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Yuhan, Bayer Korea, Yooyoung, Pharmbio Korea, Vifor Pharma, Bixink. M. Reck: Financial Interests, Personal, Advisory Role, Lectures and consultancy: Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi Sankyo, GSK, Lilly, Merck, MSD, Novartis, Pfizer, Regeneron, Roche, Samsung Bioepsis, Sanofi. Z. Szijgyarto: Financial Interests, Personal, Full or part-time Employment: GSK. N. Huseinovic: Financial Interests, Personal, Full or part-time Employment, Former employment: GSK; Financial Interests, Personal, Full or part-time Employment, Current employee: EQRx. E. Zografos: Financial Interests, Personal, Full or part-time Employment: GSK. S. O’Donnell: Financial Interests, Personal, Full or part-time Employment: GSK; Financial Interests, Personal, Full or part-time Employment, Spouse is a US government employee: US Government. F. de Marinis: Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Novartis, Merck, BMS, MSD. All other authors have declared no conflicts of interest.