Advanced non–small cell lung cancer (NSCLC) in patients whose tumors have no EGFR or ALK alterations poses a particular challenge in terms of first-line therapy. The use of nivolumab plus ipilimumab as well as nivolumab/ipilimumab plus two cycles of chemotherapy, respectively, as first-line therapy for advanced NSCLC is supported by two different trials, CheckMate 227 and CheckMate 9LA. These study results were presented at the ASCO20 Virtual Scientific Program.

Updated follow-up of CheckMate 227 at 3 years showed that nivolumab plus ipilimu­mab extended overall survival compared with chemotherapy alone in patients with PD-L1–positive (ie, ≥ 1%) tumors. An exploratory analysis also demonstrated improved overall survival with the immunotherapy combination in patients with PD-L1–negative tumors (< 1%).¹

On the basis of the primary results of CheckMate 227, the U.S. Food and Drug Administration (FDA) approved nivolumab plus ipilimumab as first-line therapy in patients with PD-L1 ≥ 1%. However, this combination may also be adopted to treat patients with PD-L1–negative disease, since they too had a significant survival benefit compared with the other two study arms.

CheckMate 9LA, with only about 12 months of follow-up, showed a survival difference favoring nivolumab/ipilimumab plus limited chemotherapy (two cycles) vs four cycles of chemotherapy as first-line therapy of NSCLC.² The survival benefit was observed across the board in PD-L1–positive and PD-L1–negative patients.

Benjamin P. Levy, MD

Commenting on these two studies, which were selected for the ASCO20 Lung Cancer Highlights Session, Benjamin P. Levy, MD, of Johns Hopkins School of Medicine, Baltimore, said: “It is challenging to compare these trials. Undoubtedly, they represent two new regimens that are options for our patients. Now we need to look beyond the tail of the curve from 3 years to 5 years to help us select the best regimen. We also need to move beyond PD-L1 as a biomarker.”

CheckMate 227

Previously published results of the randomized phase III CheckMate 227 study showed that first-line nivolumab plus ipilimumab significantly prolonged overall survival in patients with advanced NSCLC and tumor PD-L1 expression ≥ 1% (primary endpoint) and PD-L1 < 1% (prespecified descriptive analysis).³

Suresh S. Ramalingam, MD

At ASCO20, Suresh S. Ramalingam, MD, presented 3-year updated efficacy and safety results by PD-L1 expression (≥ 1% and < 1%) and the relationship of response with long-term survival for both PD-L1 groups.

“The updated analysis found that the nivolumab-plus-ipilimumab combination as front-line therapy continued to provide durable and long-term benefits vs chemotherapy for advanced NSCLC regardless of PD-L1 expression. More than one-third of all patients with a response to nivolumab plus ipilimumab remain in response at 3 years with [the combination], compared with less than 5% with chemotherapy alone,” noted Dr. Ramalingam.

The combination of nivolumab plus ipilimumab had a greater than 70% 3-year post landmark overall survival for patients who achieved a complete or partial response by 6 months of therapy with PD-L1 ≥ 1% disease, and > 80% with PD-L1 < 1% in an exploratory post–landmark overall survival analysis, Dr. Ramalingam said.

“This dual-immunotherapy regimen is a novel chemotherapy-sparing first-line treatment option that is now approved for the treatment of advanced NSCLC,” he added.

CheckMate 227 had two parts: part 1a compared nivolumab plus ipilimumab vs chemotherapy vs nivolumab in a 1:1:1 randomization in NSCLC with PD-L1 > 1% (n = 583); and part 1b randomly assigned patients who had PD-L1 < 1% NSCLC (n = 583) to nivolumab plus ipilimumab vs nivolumab plus chemotherapy vs chemotherapy alone. All patients were untreated for metastatic disease at baseline. Patients with brain metastases were excluded.

The two parts of the study were evenly balanced between PD-L1 ≥ 1% (68%) and PD-L1 < 1% (32%). Median age was 64 years.

Three-year overall survival was 33% for nivolumab plus ipilimumab vs 22% for chemotherapy in the PD-L1–positive group. Median overall survival was 17.1 months for nivolumab plus ipilimumab vs 14.9 months with chemotherapy. The hazard ratio remained unchanged from the published report, representing a 21% reduction in mortality for the immunotherapy combination. Three-year survival with nivolumab alone was 29%, and median overall survival was 15.7 months.

Three-year survival in patients with PD-L1 < 1% was 34% for nivolumab plus ipilimumab vs 20% for nivolumab plus chemotherapy vs 23% with chemotherapy alone. Median overall survival for the combination was 17.2 months compared with 12.2 months for chemotherapy alone, for a 36% reduction in mortality favoring nivolumab plus ipilimumab.

Progression-free survival results also favored the combination of nivolumab plus ipilimumab in both PD-L1 groups. In the PD-L1 ≥ 1% group, 3-year progression-free survival was 18% for nivolumab plus ipilimumab, 12% for nivolumab, and 4% for chemotherapy alone. Median progression-free survival was 5.2 months, 4.2 months, and 5.6 months, respectively.

In the group with PD-L1 < 1%, 3-year progression-free survival was 13% with nivolumab plus ipilimumab, 8% with nivolumab plus chemotherapy, and 2% with chemotherapy alone. Median progression-free survival was 5.1 months, 5.6 months, and 4.7 months, respectively.

In PD-L1–positive patients, 38% maintained response at 3 years compared with 4% in the chemotherapy arm. Median duration of response was 23.2 months compared to 6.7 months, respectively.

In the PD-L1 < 1% group, 44% maintained response at 3 years with nivolumab plus ipilimumab compared with 0% of the chemotherapy group. Median duration of response was 18 months compared to 4.8 months with chemotherapy.

“The durability of responses was substantially more favorable with the combination of nivolu­mab plus ipilimumab than with nivolumab plus chemotherapy or chemotherapy alone in the PD-L1 < 1% population,” Dr. Ramalingam stated.

A landmark analysis showed that patients who achieved complete or partial response had longer overall survival in both groups. That analysis excluded patients who died within 6 months of treatment initiation.

“Patients who achieve a response with nivolumab plus ipilimumab have a 70% chance of survival at 3 years if they are PD-L1–positive and an 83% chance of survival if they are PD-L1–negative,” Dr. Ramalingam said. There was no treatment-related difference in 3-year survival for PD-L1–positive or PD-L1–negative patients with stable disease or progressive disease as their best response.

“The nivolumab-plus-ipilimumab combination as front-line therapy continued to provide durable and long-term benefits vs chemotherapy for advanced NSCLC regardless of PD-L1 expression.”

— Suresh S. Ramalingam, MD

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At a minimum follow-up of 36.3 months, safety was similar as in the previously published results of CheckMate 227.³ There were more treatment discontinuations: 12% with nivolumab plus ipilimumab compared with 9% for chemotherapy alone. Immune-related adverse events were most frequently reported during the first 6 months of treatment, and, once past that period, the rates of autoimmune events were low.

“This supports the notion that the majority of the patients who benefit from nivolumab plus ipilimumab can complete the planned 24 months of treatment with supportive care without a substantial increase in toxicity,” Dr. Ramalingam stated.

CheckMate 9LA

“One-year follow-up of CheckMate 9LA confirmed the hypothesis that adding limited chemotherapy [two cycles] to nivolumab plus ipilimumab would provide rapid disease control while building on the durable overall survival observed with this combination in several trials,” said lead author Martin Reck, MD, Head of the Department of Thoracic Oncology at Lung Clinic Grosshansdorf, Germany, who presented results of the preplanned interim analysis.

CheckMate 9LA randomly assigned 790 patients with no targetable mutations to nivolumab plus ipilimumab plus two cycles of chemotherapy vs four cycles of chemotherapy (control arm). Participants were unselected for PD-L1 expression and were stratified for PD-L1 expression, gender, and histology. At baseline, 30% had squamous histology, and 40% were PD-L1–negative.

Martin Reck, MD

“The interim analysis of overall survival confirmed the superiority of nivolumab plus ipilimumab plus chemotherapy,” Dr. Reck said. “The survival curves separated early and didn’t cross.”

“CheckMate 9LA met the primary endpoint at a preplanned interim analysis. Nivolumab plus ipilimumab plus two cycles of chemotherapy led to clinically meaningful improvement at all efficacy endpoints, and this was increased with longer follow-up. The benefits of this regimen were consistent across all histologies and all PD-L1 levels, with no new safety signals. A limited course of chemotherapy should be considered as a new first-line opportunity for patients with advanced NSCLC,” Dr. Reck stated.

Nivolumab/ipilimumab plus limited chemotherapy was associated with a median overall survival of 14.1 months vs 10.7 months for chemotherapy alone—a 21% improvement favoring the combination arm (P = .0006). Progression-free survival also favored the combination arm.

With further follow-up of 4 months, median overall survival was 15.6 vs 10.9 months, respectively, a 34% improvement, and 1-year overall survival was 63% vs 47%. Upon disease progression, 34% of patients in the chemotherapy arm were treated with subsequent immunotherapy.

“The survival benefit was observed in the majority of prespecified subgroups, including different histologies and presence or absence of brain metastases,” he added. “Furthermore, the survival benefit was independent of PD-L1 expression level and similar in PD-L1–positive and PD-L1–negative patients.”

Overall response rates, disease control rates, and duration of response rates were all higher in the patients treated with nivolumab/ipilimu­mab plus limited chemotherapy compared with chemotherapy. However, the experimental arm had higher rates of toxicity. The rate of grade 3 to 4 treatment-related adverse events was 47% vs 38% with four cycles of chemotherapy. The discontinuation rate due to adverse events was 16% compared with 5%, respectively. Serious adverse events were reported in 25% vs 15%, respectively.

The most frequent treatment-related adverse events in the experimental arm were nausea, anemia, asthenia, and diarrhea. Chemotherapy-associated adverse events were less frequent in the limited chemotherapy arm compared with four cycles of chemotherapy. The majority of immune-related adverse events were mild to moderate, with skin toxicity being the most common, followed by endocrine effects. 

DISCLOSURE: CheckMate studies were funded by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Levy has served in a consulting or advisory role for Celgene, Genentech/Roche, Guardant Health, Lilly, Merck, Novartis, Pfizer, and Takeda; and has received institutional research funding from AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, and Turning Point Therapeutics. Dr. Ramalingam has served in a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Genentech/Roche, Lilly/ImClone, Loxo, Merck, Nektar; Takeda, and Tesaro; has received institutional research funding from AbbVie, Advaxis, AstraZeneca/MedImmune, Bristol-Myers Squibb, EMD Serono, Genmab, Merck, Pfizer, Takeda, and Vertex; and has been reimbursed for travel, accommodations, or other expenses from AstraZeneca. Dr. Reck has served in a consulting or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck Serono, MSD Oncology, Novartis, Pfizer, and Roche/Genentech; and has been a member of speakers bureaus for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck Serono, MSD Oncology, Novartis, Pfizer, and Roche/Genentech.

REFERENCES

1. Ramalingam SS, Ciuleanu TE, Pluzanski A, et al: Nivolumab plus ipilimumab versus platinum doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. ASCO20 Virtual Scientific Program. Abstract 9500.

2. Reck M, Ciuleanu TE, Dols MC, et al: Nivolumab plus ipilimumab plus 2 cycles of platinum doublet chemotherapy vs 4 cycles of chemo as first-line treatment for stage IV/recurrent non-small cell lung cancer: CheckMate 9LA. ASCO20 Virtual Scientific Program. Abstract 9501.

3. Hellman MD, Paz-Areas L Cabo RB, et al. Nivolumab plus ipilimumab in advanced non-small cell cancer. N Engl J Med 381:2020-2031, 2019.