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Nivolumab Plus Ipilimumab in First-Line NSCLC: Two New Indications, Many More Questions


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In May 2020, the combination of nivolumab and ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for two separate indications in the first-line setting of advanced non–small cell lung cancer (NSCLC). One was in metastatic NSCLC with tumors that have PD-L1 expression ≥ 1% with no EGFR or ALK mutations, and the other one is in combination with two cycles of platinum-doublet chemotherapy in metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor mutations.1,2

The ipilimumab/nivolumab regimens join a growing list of first-line immunotherapy options for patients with advanced NSCLC without a driver mutation. However, they also raise questions about patient and treatment selection.

Additional follow-up data presented during the virtual edition of the International Association for the Study of Lung Cancer (IASLC) 2020 North America Conference on Lung Cancer confirmed the overall survival benefit of the immunotherapy regimens.3,4 They suggest that novel biomarkers other than PD-L1 immunohistochemistry may be needed to optimize outcomes.

CheckMate 9LA: Additional Follow-up Shows Further Benefit

David P. Carbone, MD, PhD, Barbara J. Bonner Chair in Lung Cancer Research and Director of the James Thoracic Center at The Ohio State University Comprehensive Cancer Center, presented data from CheckMate 9LA. This is a phase III open-label, randomized study that evaluated nivolumab and ipilimumab plus two cycles of chemotherapy vs chemotherapy alone in patients with metastatic or recurrent NSCLC.3


“Nivolumab plus ipilimumab with a limited course of chemotherapy and no maintenance chemotherapy should be considered a new option for first-line treatment of advanced NSCLC.”
— David P. Carbone, MD, PhD

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As Dr. Carbone reported, CheckMate 9LA met its primary endpoint of overall survival at the preplanned interim analysis (hazard ratio [HR] = 0.69, P = .0006). The regimen was approved by the FDA in May 2020.

Of note, longer follow-up showed clinically meaningful improvement in all efficacy endpoints. With a minimum follow-up of 12 months, overall survival benefit was further improved (HR = 0.66), said Dr. Carbone. Median overall survival in the ipilimumab/nivolumab group was 15.6 months compared with 10.9 months in the chemotherapy alone group after the additional 4 months of follow-up.

The duration of response was also “impressively different” between the arms, Dr. Carbone reported. The median duration of response was 11.3 months with ipilimumab/nivolumab vs 5.6 months with chemotherapy alone.

Furthermore, the magnitude of benefit with nivolumab/ipilimumab plus two cycles of chemotherapy vs chemotherapy alone was consistent across all histologies and all PD-L1 expression levels, including the populations with PD-L1 less than 1% and between 1% and 49%.

Although patients in the ipilimumab/nivolumab arm had higher-grade toxicities and treatment-related adverse events leading to discontinuation of therapy, said Dr. Carbone, no new safety signals were observed.

Of note, early separation of the overall survival curves and lower progressive disease rates as best overall response validated the basic hypothesis of adding two cycles of chemotherapy to dual checkpoint inhibition. “These results demonstrated that nivolumab plus ipilimumab with a limited course of chemotherapy and no maintenance chemotherapy should be considered a new option for first-line treatment of advanced NSCLC,” Dr. Carbone concluded.

CheckMate 227: 3-Year Survival Benefit Confirmed

Julie Renee Brahmer, MD, Co-Director of the Upper Aerodigestive Department within the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine, presented 3-year follow-up data from CheckMate 227. This is a phase III open-label study that randomly assigned patients with advanced NSCLC to first-line treatment with nivolumab plus ipilimumab vs platinum-doublet chemotherapy.4


“More than one-third of all responders remained in response after 3 years with nivolumab plus ipilimumab compared with less than 5% with chemotherapy.”
— Julie Renee Brahmer, MD

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As Dr. Brahmer reported, previous data established that the combination immunotherapy improved overall survival in patients with both PD-L1–positive and –negative tumors, although the latter group was part of a prespecified descriptive analysis. FDA approval was granted for patients with PD-L1–positive tumors in May 2020.

During the North American Conference on Lung Cancer, Dr. Brahmer presented the results of a post-landmark overall survival analysis based on response data status at 6 months. The choice was 6 months because the majority of patients who responded to treatment did so by then, said Dr. Brahmer.

With 3-years of minimum follow-up, nivolumab/ipilimumab continued to provide durable and long-term efficacy benefits vs chemotherapy for patients with advanced NSCLC, regardless of PD-L1 expression. In patients with PD-L1 expression ≥ 1%, the 3-year overall survival rate was 33% with the immunotherapy combination vs 22% with chemotherapy alone. In patients with PD-L1–negative tumors (PD-L1 expression < 1%), the 3-year overall survival rate was 34% with nivolumab/ipilimumab vs 15% with chemotherapy alone.

KEY POINTS

  • Based on CheckMate 9LA, ipilimumab/nivolumab was approved for use with two cycles of platinum-doublet chemotherapy as first-line treatment of patients who have metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor mutations.
  • Based on CheckMate 227, ipilimumab/nivolumab was approved for first-line treatment in patients who have metastatic NSCLC with tumors that have PD-L1 expression ≥ 1%, as determined by an FDA-approved test, and no EGFR or ALK genomic tumor mutations.

“More than one-third of all responders remained in response after 3 years with nivolumab plus ipilimumab compared with less than 5% with chemotherapy,” said Dr. Brahmer.

The immunotherapy combination also continued to provide improved efficacy compared with nivolumab monotherapy and nivolumab plus chemotherapy, regardless of PD-L1 expression. Among patients with PD-L1 expression ≥ 1%, 70% of responders at 6 months in the nivolumab/ipilimumab arm were alive at 3 years vs 39% in the chemotherapy arm. For patients with PD-L1–negative tumors, 82% of responders in the ipilimumab/nivolumab arm were alive at 3 years vs 25% in the chemotherapy arm.

Finally, no new safety signals were identified for nivolumab plus ipilimumab with extended follow-up.

“This dual immunotherapy regimen is a novel chemotherapy-sparing first-line treatment option for patients with advanced NSCLC,” Dr. Brahmer concluded. 

DISCLOSURE: Dr. Carbone has been employed by the James Cancer Center; has received honoraria from AstraZeneca and Nexus Oncology; has served as a consultant or advisor to AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, EMD Serono, GlaxoSmithKline, Helsinn Therapeutics, Incyte, Inivata, Inovio Pharmaceuticals, Janssen, Kyowa Hakko Kirin, Loxo, Merck, Novartis, Pfizer, and Takeda; and has received research funding from Bristol Myers Squibb. Dr. Brahmer has received honoraria from Roche/Genentech; has served as a consultant or advisor to Amgen, Bristol Myers Squibb, Celgene, Genentech, Janssen Oncology, Lilly, Merck, and Syndax; has received research funding from Revolution; has received institutional research funding from AstraZeneca, Bristol Myers Squibb, Incyte, and Spectrum; has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb and Roche/Genentech; and has held other relationships with Bristol Myers Squibb, Janssen Oncology, and Merck.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥ 1%). Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1. Accessed November 3, 2020.

2. U.S. Food and Drug Administration: FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc. Accessed November 3, 2020.

3. Carbone DP, Reck M, Ciuleanu TE, et al: Nivolumab + ipilimumab + 2 cycles of platinum-doublet chemotherapy vs 4 cycles chemo as first-line treatment for stage IV/recurrent NSCLC: CheckMate 9LA. 2020 North America Virtual Conference on Lung Cancer. Abstract 24. Presented October 16, 2020.

4. Ramalingam SS, Ciuleanu TE, Pluzanski A, et al: Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. 2020 North America Virtual Conference on Lung Cancer. Abstract 34. Presented October 16, 2020.

 


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