Background

Despite high initial response rates, most patients (pts) with SCLC relapse soon after first-line (1L) treatment (tx), with limited tx options and a poor prognosis. Nivo is approved in the US for tx of metastatic SCLC with progression after platinum-based chemo and ≥1 other line of tx. We report results from CheckMate 331 (NCT02481830), a global, open-label, phase 3 trial of nivo vs chemo in pts with relapsed SCLC after 1L platinum-based chemo.

Methods

Pts (N = 569) with limited- or extensive-disease SCLC and recurrence/progression after 1L platinum-based chemo were randomized 1:1 to receive nivo (n = 284) or chemo (n = 285; topotecan or amrubicin where locally approved; see Table for all dosages), stratified by platinum sensitivity (90 days) and CNS metastases. Pts were treated until progression (or no longer deriving clinical benefit with nivo) or unacceptable toxicity. Primary endpoint was overall survival (OS) with nivo vs chemo. Approximately 482 events were expected, providing 90% power to detect a hazard ratio (HR) of 0.745 favoring nivo (2-sided alpha, 0.05).

Results

Minimum follow-up was 15.8 months. Baseline characteristics were balanced between arms. No statistically significant improvement in OS was seen with nivo vs chemo (HR, 0.86 [95% CI, 0.72–1.04]); however OS curves showed delayed separation after month 12. HR for OS with nivo vs chemo in pts with platinum-resistant SCLC was 0.71 (95% CI, 0.54–0.94). Other efficacy outcomes are shown in the table. All-grade (grade 3–4) tx-related adverse events (AE) occurred in 55% (14%) of nivo- and 90% (73%) of chemo-treated pts. There were 2 tx-related deaths with nivo and 3 with chemo.

Table: LBA5

Efficacy outcomes with nivolumab vs chemotherapy in recurrent SCLC

Conclusions

CheckMate 331 did not meet the primary endpoint of OS for nivo vs chemo in 2L SCLC. However, late separation of curves and potential activity in the platinum-refractory setting suggests possible long-term benefit for some pts. There were no new safety signals, with lower AE rates observed with nivo.

Editorial acknowledgement

Writing and editorial assistance was provided by Nicole Draghi, PhD, of Caudex, funded by Bristol-Myers Squibb.

Clinical trial identification

NCT02481830.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

M. Reck: Lecture and consultant fees: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. T. Ciuleanu: Advisory role: Amgen, Astellas, AZ, BMS, Boehringer Ingelheim, Eli Lilly, GSK, Janssen, Merck Serono, MSD, Novartis, Pfizer, Roche, Sanofi. Personal fees: Amgen, Boehringer Ingelheim, Ipsen, Janssen, Merck Serono, Pfizer, Roche, Sanofi, Servier. S. Gettinger: Non-financial support: Millennium Pharmaceuticals, Inc.; Grants and personal fees: Ariad/Takeda, Bristol-Myers Squibb; Personal fees: Janssen; Grants: Genentech/Roche, Incyte, Iovance. S. Peters: Honoraria or consultation fees: AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda; Talk in company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp and Dohme, Novartis, Pfizer, Takeda; Grants/research supports: (Sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche, Illumina, Merck Sharp and Dohme, Merck Serono, Novartis, Pfizer. L. Horn: Personal fees: AbbVie, AstraZeneca, Merck, Incyte, Xcovery, Genentech, EMD Serono. C. Audigier-Valette: BMS, Roche, AstraZeneca, AbbVie, MSD, Novartis, Pfizer, Takeda, Lilly. N. Pardo: Pzifer, Boeheringer Ingelheim, Roche. O. Juan-Vidal: Honoraria or advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Roche/Genetech, AstraZeneca, Pfizer, Eli Lilly, AbbVie. Institutional research funding: Bristol-Myers Squibb, AstraZeneca. J. Wolf: Advisory boards and lecture fees: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly, MSD, Novartis, Pfizer, Roche; Research support (to institution): BMS, MSD, Novartis, Pfizer. S.J. Antonia: Personal fees: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck; Stock ownership: Cellular Biomedicine Group. K. Nakagawa: Grants and personal fees: Daiichi Sankyo, Astellas Pharma, AstraZeneca, EPS Holdings, Ono, Kyowa Hakko Kirin, Chugai, Nippon Boehringer Ingelheim, Eli Lilly, Pfizer, Bristol-Myers Squibb, Novartis, Taiho; Grants: Quintiles, Japan Clinical Research Operations, Eisai, PPD-SNBL K.K., Takeda, AbbVie, Yakult Honsha, Parexel, Otsuka, AC Medical, Merck Serono; Personal fees: Showa Yakuhin Kako, SymBio Pharmaceuticals, MSD K.K., Ayumi Pharmaceutical Corporation. G. Selvaggi, C. Baudelet, H. Chang: Employment: Bristol-Myers Squibb. D.R. Spigel: Research grants: AstraZeneca; Advisory role (paid to institution): AstraZeneca; Research and advisory role (paid to institution): Bristol-Myers Squibb, Roche/Genentech, Pfizer, Merck. All other authors have declared no conflicts of interest.

Background

Durvalumab (D), a human IgG1 mAb against PD-1 and CD80, has shown clinical activity in patients (pts) with non-small cell lung cancer (NSCLC). Tremelimumab (T) is a human IgG2 mAb against CTLA-4. D+T has previously also shown durable responses in metastatic NSCLC (mNSCLC). MYSTIC (NCT02453282) was an open-label, Phase 3 trial of first-line treatment with D vs platinum-based doublet chemotherapy (CT) and D+T vs CT in mNSCLC.

Methods

Eligible pts had mNSCLC; were immunotherapy/chemotherapy-naïve; and had no EGFR sensitising mutation or ALK rearrangement. Tumour cell (TC) PD-L1 expression (≥25% vs <25%) and histology were stratification factors. Patients were randomised (1:1:1) to D (20 mg/kg i.v. q4w); D+T (D: 20 mg/kg i.v. q4w; T: 1 mg/kg i.v. q4w [up to 4 doses]); or CT (intended up to 6 cycles; pemetrexed maintenance permitted in eligible pts) until disease progression. Primary endpoints were overall survival (OS) for D vs CT and OS and progression free survival (PFS; blinded independent central review [RECIST v1.1]) for D+T vs CT in pts with PD-L1 TC expression ≥25%, defined by the VENTANA PD-L1 (SP263) assay. Data cutoffs were 4 Oct 2018 (OS and safety) and 1 Jun 2017 (PFS).

Results

1118 pts were randomised. Baseline characteristics were balanced. Efficacy findings are presented for the 488 pts with PD-L1 TC ≥25%. Median OS was 16.3 vs 12.9 months for D vs CT (HR 0.76 [97.54% CI, 0.564, 1.019]; p=0.036) and 11.9 vs 12.9 months for D+T vs CT (HR 0.85 [98.77% CI, 0.611, 1.173]; p=0.202). Median PFS was 3.9 vs 5.4 months for D+T vs CT (HR 1.05 [99.5% CI, 0.722, 1.534]; p=0.705). 39.5% pts in the CT arm received subsequent immunotherapy after treatment discontinuation vs 6.1% and 3.1% pts in the D and D+T arms. Incidence of Grade 3/4 treatment-related AEs was 14.6%, 22.1% and 33.8% with D, D+T and CT, respectively. Efficacy based on additional PD-L1 cutoffs will be presented.

Conclusions

In pts with mNSCLC, while statistical significance was not achieved for primary OS and PFS endpoints, first-line D demonstrated clinically meaningful improvement in OS vs CT (PD-L1 TC ≥25%). Safety data were consistent with the known safety profiles of D+/-T. Further analyses are ongoing.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Rebecca Douglas, PhD, of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca.

Clinical trial identification

NCT02453282 (release date: May 25, 2015).

Legal entity responsible for the study

AstraZeneca plc.

Funding

AstraZeneca.

Disclosure

N.A. Rizvi: Advisory boards: Abbvie, AZ, BMS, EMD Serono, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Neogenomics, Oncomed, Gritstone, Bellicum; Equity: Oncomed, Gritstone, Bellicum, ARMO; Royalties: PGDX. B. Chul Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD Consultancy: Novartis, AZ, BI, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Stock: TheraCanVac, Inc. N. Reinmuth: Personal fees: AstraZeneca, Roche, Boehringer-Ingelheim, Takeda, MSD, BMS, Novartis, Pfizer, Merck. A. Smolin: Grants: AstraZeneca; Grants and personal fees: AstraZeneca, Roche, MSD, BMS; Personal fees: BIOCAD, Boehringer-Ingelheim. S.J. Antonia: Advisory board/contracted research: BMS, Novartis, Merck, CBMG, Boehringer-Ingelheim, AstraZeneca/MedImmune, Memgen, FLX Bio, Nektar, Venn. G. Robinet: Grants and personal fees: AstraZeneca; Grants and personal fees: MSD; Personal fees: Boehringer-Ingelheim. R. Natale: Spouse: Employee (Medical Science Liaison) of AZ (salary/compensation completely unrelated to the contracted research work performed at my institution that is the subject of the submitted abstract). K. Nakagawa: Research funding: GlaxoSmithKline K.K., AstraZeneca K.K., Kyowa Hakko Kirin, Pfizer Japan Inc., AbbVie Inc., Novartis Pharma K.K., Nippon Boehringer-Ingelheim, Daiichi Sankyo, Eli Lilly Japan K.K., MSD K.K., Quintiles Inc., Ono Pharmaceutical, BMS, EPS International, Chugai Pharmaceutical, ICON Japan K.K., Gritstone Oncology, Inc., Linical, Yakult Honsha, Parexel International Corp., Otsuka Pharmaceutical, Astellas Pharma Inc., AC Medical Inc., Taiho Pharmaceutical, Merck Serono, EPS Associates, Quintiles Inc., Japan Clinical Research Operations, Eisai, PPD-SNBL K.K., Takeda Pharmaceutical, Covance Inc., inVentiv Health Japan, A2 Healthcare Corp., EP-CRSU; Honoraria: Astellas Pharma Inc., AstraZeneca K.K., Novartis Pharma K.K., Pfizer Japan Inc., Chugai Pharmaceutical, Ono Pharmaceutical, Nippon Boehringer-Ingelheim, BMS, Kissei Pharmaceutical, Eli Lilly Japan K.K., MSD K.K., EPS Holdings Inc., Showa Yakuhin Kako, Clinical Trial, CareNet, Inc., Nikkei Business Publications, Inc., Nichi-Iko Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ayumi Pharmaceutical Corporation, Kyowa Hakko Kirin, Sym Bio Pharmaceuticals, Medicus Shuppan Publishers, Reno Medical K.K., Yodosha, Nanzando; Consulting or advisory role: Astellas Pharma Inc., Eli Lilly Japan K.K., Ono Pharmaceutical, Takeda Pharmaceutical. L. Zhao: Full time employment: AstraZeneca. P.K. Stockman: Full-time employee, stock ownership: AstraZeneca. V. Chand: Full-time employment: AstraZeneca; stock ownership: BMS. S. Peters: Personal fees: Abbvie, Amgen, AZ, Bayer, Biocartis, BI, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda; Non-financial support: Amgen, AZ, BI, BMS, Clovis, F. Hoffmann-La Roche, Illumina, MSD, Merck Serono, Novartis, Pfizer. All other authors have declared no conflicts of interest.