Background

Osi, a third-generation, central nervous system-active EGFR-tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI sensitising and EGFR T790M resistance mutations. In the Phase 3 FLAURA2 study (NCT04035486), 1L osi + platinum-pemetrexed chemotherapy (CTx) significantly improved progression-free survival (PFS) vs osi alone in patients (pts) with EGFRm advanced NSCLC (HR 0.62; 95% CI 0.49, 0.79; p<0.001).¹ Here we report post-progression outcomes, including updated overall survival (OS), from FLAURA2.

Methods

Adult pts with treatment-naïve EGFRm (Exon 19 deletion/L858R) advanced NSCLC and WHO performance status 0/1 received osi 80 mg once daily (QD) + CTx (pemetrexed + cisplatin or carboplatin for 4 cycles every 3 weeks [Q3W]), then osi 80 mg QD + pemetrexed Q3W, or osi 80 mg QD monotherapy until progression/discontinuation criterion. Subsequent therapy (tx) was per investigator choice. Secondary endpoints included time from randomisation to first subsequent tx (TFST), time to second progression (PFS2), time to second subsequent tx (TSST) and OS. Data cutoff (DCO): 3 Apr 2023. We report a second interim analysis (IA) of updated OS (DCO: 8 Jan 2024).

Results

At primary DCO (3 Apr 2023), 123/279 (44%) vs 151/278 (54%) pts had discontinued osi + CTx vs osi. Among these pts, 57/123 (46%; osi + CTx) vs 91/151 (60%; osi) began a FST, most commonly CTx in 37/57 (65%) vs 75/91 (82%) pts. TFST, PFS2,¹ and TSST HR (95% CI) were 0.73 (0.56, 0.94), 0.70 (0.52, 0.93) and 0.69 (0.51, 0.93), respectively. While OS results remained immature and statistical significance was not reached at the second IA analysis (41% maturity; DCO: 8 Jan 2024), a trend towards OS benefit was observed. Median OS was not reached (95% CI 38.0, not calculable [NC]) with osi + CTx and 36.7 months (95% CI 33.2, NC) with osi; OS HR was 0.75 (95% CI 0.57, 0.97). OS was consistent across predefined subgroups.

Conclusions

These FLAURA2 post-progression results demonstrate that 1L osi + CTx provides clinical benefit beyond initial progression vs osi for pts with EGFRm advanced NSCLC, with updated OS data showing an encouraging trend towards OS benefit. 1. Planchard et al. NEJM 2023;389:1935–48.

Clinical trial identification

NCT04035486.

Editorial acknowledgement

The authors would like to acknowledge Jenny Wilkinson, PhD, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

I. Okamoto: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca. B.G.M. Hughes: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Pfizer, Eisai, Sanofi; Financial Interests, Personal, Principal Investigator: AstraZeneca, Merck Sharp and Dohme, Bristol Myers Squibb, Roche, Pfizer, BeiGene, Sanofi. S. Ahmed: Financial Interests, Personal, Other, Consulting fee: AstraZeneca; Financial Interests, Personal, Other, Lecture fees: AstraZeneca. K.H.H. Lee: Other, Personal and Institutional, Research Grant: Merck; Other, Personal and Institutional, Advisory Role: Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Eli Lilly, AstraZeneca, Yuhan. S. Oizumi: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Chugai Pharmaceutical Co., Ltd., Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Ono Pharmaceutical Co., Ltd., Pfizer, Merck Sharp & Dohme, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical. M. Ahn: Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Merck Sharp & Dohme, Merck, Takeda, Ono Pharmaceutical Co., Ltd., Novartis, Lilly, Amgen, Yuhan Pharmaceutical; Financial Interests, Personal, Advisory Role: AstraZeneca, Roche, Merck Sharp & Dohme, Merck, Takeda, Ono Pharmaceutical Co., Ltd., Novartis, Lilly, Amgen, Yuhan Pharmaceutical, Alpha Pharmaceuticals. Y. Tambo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai Pharmaceutical, Taiho, Merck Sharp & Dohme, Pfizer, Kyowa Kirin. R.K. Li: Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis, ZPT Amgen, ZPT Eli Lilly, Pfizer; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Novartis, ZPT Amgen, ZPT Eli Lilly, Pfizer. A. Todd: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. D. Kulkarni: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca; Financial Interests, Institutional, Stocks/Shares: AstraZeneca. N.P. Amin: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen, Seagen, Gilead, Pierre Fabre; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen; Non-Financial Interests, Personal, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre; Non-Financial Interests, Personal, Principal Investigator: AbbVie, Sanofi, Janssen. P.A. Jänne: Financial Interests, Institutional, Research Grant: Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Takeda; Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, Biocartis, Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Duality Biologics, Eli Lilly, Frontier Medicines, Hongyun Biotechnology, Ignyta, Loxo Oncology, Merus, Mirati Therapeutics Inc., Monte Rosa, Novartis, Pfizer, PUMA, Roche/Genentech, Sanofi, Scorpion Therapeutics, SFJ Pharmaceuticals, Silicon Therapeutics, Takeda, Transcenta, Voronoi, Allorion Therapeutics, Accutar Biotech, AbbVie, Blueprint Medicines; Financial Interests, Personal, Other, Co-inventor on a DFCI patent licensed to Lab Corp.: Patent; Financial Interests, Personal, Royalties, DFCI owned IP licensed to Lab Corp.: Intellectual Property. All other authors have declared no conflicts of interest.

Background

RATIONALE-315 (NCT04379635) investigated the efficacy and safety of perioperative tislelizumab (TIS) or placebo (PBO) with neoadjuvant chemotherapy (CT) in patients (pts) with resectable NSCLC. Here, we report key surgery outcomes from the study.

Methods

Pts in China with treatment-naïve resectable stage II-IIIA NSCLC, with ECOG PS ≤1 and no known EGFR mutations or ALK gene translocations were enrolled. Pts were randomized (1:1) to 3-4 cycles of TIS 200 mg or PBO, IV Q3W, plus CT, followed by surgery and up to 8 cycles of adjuvant TIS 400 mg or PBO, IV Q6W. Primary endpoints were major pathological response (MPR, reported previously) and event-free survival. Key secondary endpoint was pathological complete response (pCR) rate. Surgery outcomes were exploratory endpoints.

Results

453 pts were enrolled and baseline characteristics were similar between arms. 190/226 pts (84.1%) in the TIS arm and 173/227 pts (76.2%) in the PBO arm underwent definitive surgery (Table). Main reasons for surgery cancellation were pt withdrawal (20 vs 28 pts), progressive disease (6 vs 17 pts) and adverse events (AEs) (6 vs 2 pts), respectively. Surgery delays occurred in 31 (16.3%) vs 22 (12.7%) pts, mainly due to AEs in 12 (6.3%) vs 6 (3.5%) pts in TIS vs PBO arms, mostly within two weeks. R0 resection was achieved in 95.3% pts in TIS vs 93.1% in PBO arm. Median duration of surgery (2.7 vs 2.8 hours) and length of hospitalization (7 vs 7 days) were similar between arms. In the TIS vs PBO arms, any-grade AEs and grade ≥3 post-operative complication rates were 63.7% vs 61.3%, and 11.1% vs 15.6%, and 90-day post-surgery mortality was 3 pts (1.3%) vs 4 pts (1.8%), respectively.

Table: 108O

Types and approaches of surgery in the RATIONALE-315 study

Conclusions

Perioperative TIS plus neoadjuvant CT did not impact the feasibility and completeness of surgery and was accompanied by statistically significant improvement in MPR and pCR, and manageable safety, indicating TIS is a perioperative treatment option for pts with resectable NSCLC.

Clinical trial identification

NCT04379635.

Editorial acknowledgement

This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Yee Theng Soo, MSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd.

Legal entity responsible for the study

BeiGene, Ltd.

Funding

BeiGene, Ltd.

Disclosure

B. Yao, S. Wang: Financial Interests, Institutional, Full or part-time Employment: BeiGene (Beijing) Co., Ltd, Beijing, China; Financial Interests, Institutional, Stocks/Shares: BeiGene (Beijing) Co., Ltd, Beijing, China. R. Wang: Financial Interests, Personal, Full or part-time Employment: BeiGene; Financial Interests, Personal, Stocks/Shares: BeiGene. All other authors have declared no conflicts of interest.

Background

The PACIFIC trial established consolidation durvalumab (D) after chemoradiotherapy (CRT) as SoC for pts with unresectable stage III NSCLC. However, up to 30% of pts are ineligible due to progression during/shortly after CRT or inadequate recovery from CRT-related toxicity. The phase III PACIFIC-2 trial evaluated D initiated concurrently with platinum-based concurrent CRT (cCRT) followed by consolidation D, compared with cCRT alone, in pts with unresectable stage III NSCLC.

Methods

PACIFIC-2 (NCT03519971) was a randomized double-blind study. Treatment (Tx)-naïve pts with WHO PS 0/1 and histologically/cytologically confirmed stage III NSCLC were randomized (2:1) to receive SoC cCRT concurrently with D or placebo (PBO) IV Q4W, stratified by age and disease stage. Pts then received consolidation D/PBO until progression, unacceptable toxicity, consent withdrawal, or other discontinuation criteria. The primary endpoint was PFS (BICR; RECIST v1.1).

Results

327/328 randomized pts received Tx (D arm, n=219; PBO arm, n=108). A higher % of pts in the D vs PBO arm had T4 tumors (57.5% vs 48.6%) and squamous histology (55.3% vs 47.7%). As of 7 Sep 2023 (data cutoff), median follow-up in all (censored) pts was 30.5 (55.5) months. There was a trend (not statistically significant) toward improved PFS with D vs PBO (HR, 0.85; 95% CI: 0.65–1.12; P=0.247); median PFS was 13.8 vs 9.4 months. There was no significant difference in OS (HR, 1.03; 95% CI: 0.78–1.39; P=0.823); median OS was 36.4 vs 29.5 months. Max grade 3/4 any-cause AEs occurred in 53.4% vs 59.3% with D vs PBO; 25.6% vs 12.0% had AEs that led to discontinuation of D/PBO (14.2% vs 5.6% in the first 4 months); 47.0% vs 51.9% had serious AEs; and 13.7% vs 10.2% had AEs with outcome of death. Pneumonitis/radiation pneumonitis occurred in 28.8% vs 28.7%.

Conclusions

In PACIFIC-2, concurrent D and CRT did not improve outcomes vs CRT alone. Overall, safety and tolerability were consistent with the known profiles for D and CRT, although one quarter of pts had AEs leading to discontinuation of D, the majority of which occurred in the first 4 months. Consolidation D remains SoC for pts with unresectable stage III NSCLC who do not progress on definitive CRT.

Clinical trial identification

NCT03519971 (release date: May 9, 2018).

Editorial acknowledgement

Medical writing support for the development of this abstract, under the direction of the authors, was provided by Andrew Gannon of Ashfield MedComms (New York, NY, USA), an Inizio company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J.D. Bradley: Non-Financial Interests, Personal, Advisory Board: Varian Medical Systems, Inc, Mevion Medical Systems, AstraZeneca, Inc, Genentech, Inc; Financial Interests, Institutional, Research Grant: Varian Medical Systems, Inc; Non-Financial Interests, Institutional, Principal Investigator: PACIFIC 2 with AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator: FLASH RT Spinal Cord Toxicity in a minipig model with Varian. S. Sugawara: Financial Interests, Personal, Speaker’s Bureau: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Kyowa Kirin, Lilly, Merck, Merck Sharp & Dohme K.K., Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis; Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer, Taiho Pharmaceutical Co., Ltd., Takeda, Thermo Fisher Scientific, Towa Pharmaceutical, Sysmex Corp., Eisai Co., Ltd.; Financial Interests, Institutional, Principal Investigator: AnHeart, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo, Merck Sharp & Dohme K.K., Nippon Boehringer Ingelheim., Ono Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Principal Investigator: AbbVie, Amgen, Taiho Pharmaceutical Co., Ltd., Takeda, Accerise, Parexel International Inc.. K.H.H. Lee: Non-Financial Interests, Personal, Advisory Board: BMS, Eli Lilly, AstraZeneca, Merck, MSD, Yuhan, Pfizer; Non-Financial Interests, Personal and Institutional, Funding: Merck. A. Demirkazik: Non-Financial Interests, Personal, Principal Investigator: AstraZeneca. V. Sriuranpong: Financial Interests, Personal, Other, Honoraria: Novartis, AstraZeneca, Roche, Pfizer, MSD Oncology, Amgen, Takeda, Eisai; Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Roche, Amgen, MSD Oncology, Astellas Pharma; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, MSD Oncology, Takeda, Amgen; Financial Interests, Personal, Other, Travel, accommodations, expenses: Eisai, Roche, AstraZeneca. A. Gelatti: Financial Interests, Personal, Invited Speaker: Roche, MSD, BMS, AstraZeneca, Pfizer, Boehringer-Ingelheim, Bayer, Lilly, Novartis, Amgen, Takeda, Novartis, Daiichi Sankyo, Sanofi; Financial Interests, Personal, Advisory Board: MSD, Roche, BMS, Boehringer Ingelheim, AstraZeneca, Amgen, Bayer, Lilly, Novartis, Takeda, Beigene, Daiichi Sankyo, Pfizer, Sanofi; Financial Interests, Personal, Member of Board of Directors: AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Principal Investigator: MSD, BMS, AstraZeneca, Roche, IRxs, Janssen, Lilly, GSK, Novartis, Daiichi Sankyo, Gilead, Beigene, Boehringer Ingelheim, Amgen. J. Menezes: Financial Interests, Personal, Invited Speaker: BMS; Non-Financial Interests, Personal, Principal Investigator: BMS, AstraZeneca, MSD. B. Zurawski: Financial Interests, Personal, Other: Honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GSK, Janssen-Cilag, MSD, and Roche. M. Newton, P. Chander: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N. Jia: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. Z.F. Bałdyga-Bielecka: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. All other authors have declared no conflicts of interest.

Background

CONVERT was a phase III international randomized clinical trial comparing once-daily (OD) and twice-daily (BD) radiation therapy (RT). This updated analysis describes the 6.5 year outcomes of these regimes delivered with conformal techniques.

Methods

The CONVERT trial randomized patients 1:1 between OD RT (66 Gy/33 fractions/6.5 weeks) and BD RT (45 Gy/30 fractions/3 weeks) both delivered with concurrent cisplatin/etoposide. Three-dimensional conformal RT was mandatory, intensity-modulated RT was permitted, and elective nodal irradiation was not allowed. Prophylactic cranial irradiation was delivered at the discretion of treating clinicians. RT treatment planning was subject to central quality assurance.

Results

547 patients were recruited at 73 centres. The median follow-up for the surviving cohort (n=164) was 81.2 months. The median survival for the OD and BD arms were 25.4 months (95%CI 21.1–30.9) and 30.0 months (95%CI 25.3–36.5), HR 1.13 (95%CI 0.92–1.38), p=0.247. Performance status and tumour volume were associated with survival on multivariate analysis. No treatment-related deaths occurred subsequent to the initial analysis performed in 2017. Regarding late toxicity, 7 patients in the OD arm developed grade 3 esophagitis, 4 of which went on to develop stricture or fistulation, compared with no patients in the BD arm. Grade 3 pulmonary fibrosis occurred in 2 and 3 patients in the OD and BD arms respectively.

Conclusions

As the CONVERT trial did not demonstrate the superiority of OD RT and this regime had a slightly worse toxicity profile after 80 months of follow-up, 45 Gy BD should remain the standard of care in limited stage small cell lung cancer.

Clinical trial identification

NCT00433563.

Legal entity responsible for the study

The Christie NHS Foundation Trust.

Funding

Cancer Research UK, French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer.

Disclosure

G. Walls: Financial Interests, Personal, Invited Speaker: AstraZeneca. C. Le Pechoux: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Amgen, Janssen, Varian, MSD, Roche. C. Faivre-Finn: Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca, MSD/Merck, Elekta. All other authors have declared no conflicts of interest.