Geneva, Switzerland, 11 April 2019 - Maintenance immunotherapy fails to improve survival in extensive-stage small cell lung cancer (SCLC), according to late-breaking results from the CheckMate 451 study to be presented today at the European Lung Cancer Congress (ELCC) 2019. (1)
Around 60-70% of patients with SCLC have extensive disease at the time of diagnosis, meaning it has spread beyond a single lung and nearby lymph nodes and cannot be treated with radiotherapy. Most patients respond to chemotherapy, but the duration of the response is usually short, and their cancer grows within a short period of time. The standard approach after chemotherapy is to wait until the tumour grows before intervening. This study examined whether acting earlier, by giving maintenance immunotherapy after successful chemotherapy, would improve overall survival.
The study enrolled 834 patients with extensive-stage SCLC whose cancer did not progress after four cycles of chemotherapy. Patients were randomly allocated in a 1:1:1 ratio to combination immunotherapy with nivolumab and ipilimumab, nivolumab alone, or placebo. Patients were treated for two years or until cancer progression, death, or unacceptable toxicity.
Compared to placebo, overall survival was not significantly prolonged with combination immunotherapy (the primary endpoint) or with nivolumab alone. Study author Professor Taofeek Owonikoko, Co-Chair of the Clinical and Translational Review Committee, Winship Cancer Institute of Emory University, Atlanta, US, said the finding was "a big disappointment".
But he added: "There was some indication that compared to placebo, it took longer for the cancer to progress in patients who received either combination immunotherapy or nivolumab alone. This was not the primary endpoint of the study so we cannot make definitive conclusions, but it shows that this strategy could be promising, especially in patients who are responsive to immunotherapy. The challenge will be how to select and identify those patients since patients who began maintenance therapy sooner after completion of chemotherapy did appear to derive greater benefit."
Adverse event rates were 86% with nivolumab plus ipilimumab, 61% with nivolumab, and 50% with placebo. Rates of discontinuation due to toxicity were 31% with combination immunotherapy, 9% with nivolumab, and less than 1% with placebo. Treatment-related deaths occurred in seven (2.5%) patients on nivolumab plus ipilimumab, one patient on nivolumab, and one patient on placebo.
Commenting on the results, Dr Pilar Garrido, co-chair of this year's ELCC Congress, said: "This appears to be the end of the story for maintenance immunotherapy in unselected SCLC patients. A previous smaller study was also negative. (2) Although the progression-free survival results seem positive, the design of the study means they cannot be considered because the primary endpoint was negative. On top of that, there is concern about deaths and stopping treatment because of toxicity."
Garrido, who is head of the Thoracic Tumour Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain, said there are specific challenges related to translational research in small cell lung cancer. "SCLC is a 'recalcitrant' disease and research in this field is particularly challenging, for several reasons, including the rapid pace at which the disease progresses and the limited availability of tissue," noted Garrido. Although there are some positive data, the final role of immune checkpoint inhibitors will be shaped by the results of ongoing trials.
Predictive biomarkers will be crucial for identifying SCLC patients with small cell lung cancer who could be treated with immune checkpoint inhibitors and should be assessed within prospective studies to better understand the complexity of the immune response.
As for whether there could be a subset who responds to maintenance treatment, she said: "The study is negative and with the information available it seems difficult to say. The commitment with high quality research is key because we desperately need new options for our SCLC patients," Garrido concluded.
Notes to Editors
Please make sure to use the official name of the meeting in your reports: European Lung Cancer Congress (ELCC) 2019 Official Congress hashtag: #ELCC19
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1 Abstract LBA-1_PR 'Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study' will be presented by Taofeek Owonikoko during the Proffered Paper Session on Thursday, 11 April, 14:45 to 16:15 (CEST) in Room B. Annals of Oncology, Volume 30, 20019 Supplement 2. doi:10.1093/annonc/mdz072
2 Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). J Clin Oncol. 2017;35:8504. doi:10.1200/JCO.2017.35.15_suppl.8504.
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About the International Association for the Study of Lung Cancer (IASLC)
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LBA1_PR - Nivolumab (nivo) plus ipilimumab (ipi), nivo, or placebo (pbo) as maintenance therapy in patients (pts) with extensive disease small cell lung cancer (ED-SCLC) after first-line (1L) platinum-based chemotherapy (chemo): Results from the double-blind, randomized phase III CheckMate 451 study
T.K. Owonikoko1, H.R. Kim2, R. Govindan3, N. Ready4, M. Reck5, S. Peters6, S.R. Dakhil7, A. Navarro8, J. Rodriguez-Cid9, M. Schenker10, J.S. Lee11, V. Gutierrez12, I. Percent13, D. Morgensztern3, J. Fairchild14, C. Baudelet14, K. Park15
1Winship Cancer Institute of Emory University, Atlanta, GA, USA, 2Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea, 3Washington University Medical School, St. Louis, MO, USA, 4Duke University Medical Center, Durham, NC, USA, 5Thoracic Oncology, Krankenhaus Grosshansdorf, Grosshansdorf, Germany, 6Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois - CHUV, Lausanne, Switzerland, 7Cancer Center of Kansas, Wichita, KS, USA, 8Vall d'Hebron University Hospital, Barcelona, Spain, 9Centro Oncológico, Médica Sur, Mexico City, Mexico, 1Centrul de Oncologie Sf Nectarie, Craiova, Romania, 11Seoul National University Bundang Hospital, Seoul, Republic of Korea, 12Hospital Carlos Haya de Malaga, Malaga, Spain, 13Florida Cancer Specialists, Punta Gorda, FL, USA, 14Bristol-Myers Squibb, Princeton, NJ, USA, 15Division of Haematology/Oncology, Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
Background: In pts with ED-SCLC, response rates to 1L platinum-based chemo are high but lack durability. Treatments (txs) that prolong response duration and improve survival are needed. CheckMate 451 (NCT02538666) is a global, double-blind, phase 3 study of nivo+ipi or nivo vs pbo as maintenance therapy in pts with ED-SCLC who did not progress on 1L platinum-based chemo.
Methods: Pts (N = 834) with ED-SCLC, ECOG performance status (PS) less than or equal to 1 and response or stable disease after 4 cycles of 1L platinum-based chemo were randomized 1:1:1 (3-9 weeks from last dose of 1L chemo or 3-11 weeks for pts who received prophylactic cranial irradiation [PCI]) to nivo 1 mg/kg + ipi 3 mg/kg Q3W intravenously (IV; 4 doses followed by nivo 240 mg Q2W IV; n = 279), nivo 240 mg Q2W IV (n = 280), or pbo (n = 275), stratified by PS, sex and prior PCI. Pts were treated up to 2 years or until progression or unacceptable toxicity. Primary endpoint was overall survival (OS) for nivo+ipi vs pbo. Secondary endpoints included OS for nivo vs pbo and progression-free survival (PFS) per blinded independent central review for nivo+ipi vs pbo and nivo vs pbo.
Results: Minimum study follow-up was 9 months. Baseline characteristics were balanced between arms. OS was not significantly prolonged with nivo+ipi vs pbo (HR, 0.92; 95% CI 0.75-1.12; P = 0.3693). OS was also not prolonged for nivo vs pbo (HR, 0.84; 95% CI 0.69-1.02), although not formally tested due to statistical hierarchy. PFS HRs vs pbo were: nivo+ipi, 0.72 (0.60-0.87); nivo, 0.67 (0.56-0.81). Rates of all-grade (grade 3-4) tx-related adverse events were: nivo+ipi, 86% (52%); nivo, 61% (12%); pbo, 50% (8%). Rates of discontinuation due to tx toxicity were: nivo+ipi, 31%; nivo, 9%; pbo, <1%. Tx-related deaths were: nivo+ipi, 7 (2.5%); nivo, 1 (<1%); pbo, 1 (<1%).
Conclusions: In CheckMate 451, maintenance therapy with nivo+ipi (primary endpoint) or nivo did not prolong OS vs pbo for ED-SCLC patients who did not progress on 1L chemo. Safety profiles of nivo+ipi and nivo were consistent with previous reports at this dose/schedule in SCLC.
Clinical trial identification: NCT02538666; Release date: 2 September 2015
Editorial acknowledgement: Writing and editorial assistance was provided by Cristina Tomas, PhD, of Caudex and funded by Bristol-Myers Squibb
Legal entity responsible for the study: Bristol-Myers Squibb
Funding: Pharmaceutical, biotech, or other commercial company- Bristol-Myers Squibb
Disclosure: T.K. Owonikoko: Research support: AbbVie, Adaptimmune, Amgen, AstraZeneca, Bristol-Myers Squibb, Corvus, G1 Therapeutics, Novartis, Pfizer, Regeneron/Sanofi; Advisory board: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly/Armo, PharmaMar, Xcovery; IRC/DSMB: EMD Serono, Roche/Genentech; Co-founder: Cambium Oncology. H.R. Kim: Speakers bureau, honoraria: AstraZeneca, ONO/Bristol-Myers Squibb; Consultant: Roche. R. Govindan: Consultant/advisory committees: AbbVie, Adaptimmune, AstraZeneca, Celgene, Ignyta, Inivata, Merck, Nektar, Pfizer, Roche. N. Ready: Advisor: AbbVie, G1 therapeutics, Merck, Novartis; Advisor/speaker: Bristol-Myers Squibb, Celgene; Education: AstraZeneca, EMD Serrano, Tesaro. M. Reck: Honoraria for lectures and consultancy: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Peters: Honoraria, education grants, consultancy, attended advisory boards, and/or provided lectures: 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, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda. A. Navarro: Advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche; Safety committee member: Oryzon Genomics; Travel support: Boehringer Ingelheim, Pfizer. J. Rodriguez-Cid: Investigational resources: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, MSD, Novartis, Roche, Takeda; Advisory role: AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, MSD, Novartis, Pfizer, Roche, Takeda; Speaker role: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, Takeda. M. Schenker: For clinical trial participation (as PI/SI) my institution and I have received funds from: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bioven, Bristol-Myers Squibb, Eisai, Eli Lilly, Gilead, Merck Serono, MSD, Mylan, Nano Carrier, Novartis, Pfizer, PharmaMar, Regeneron, Roche, Samsung. D. Morgensztern: Advisory board: AbbVie, Bristol-Myers Squibb, PharmaMar, Takeda. J. Fairchild: Stock ownership: Bristol-Myers Squibb. C. Baudelet: Employee: Bristol-Myers Squibb. K. Park: Advisor: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.