FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-Small Cell Lung Cancer, a Collaborative Project Orbis Review

Abstract

On May 26, 2020, the U.S. Food and Drug Administration (FDA) approved nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. The approval was based on results from Study CA2099LA (CheckMate 9LA), an open-label trial in which 719 patients with NSCLC were randomized to receive nivolumab with ipilimumab and two cycles of chemotherapy (n=361) or four cycles of platinum-doublet chemotherapy (n=358). Overall survival (OS) was improved for patients who received nivolumab with ipilimumab and chemotherapy, with a median OS of 14.1 months (95% CI: 13.2, 16.2) compared to 10.7 months (95% CI: 9.5, 12.5) for patients who received chemotherapy (HR 0.69; 96.71% CI: 0.55, 0.87; p = 0.0006). Progression-free survival (PFS) and overall response rate (ORR) per blinded independent central review (BICR) were also statistically significant. This was the first NSCLC application reviewed under FDA’s Project Orbis, in collaboration with Singapore’s Health Sciences Authority (HSA), Australia’s Therapeutic Goods Administration (TGA), and Health Canada (HC). The benefit-risk analysis supports FDA’s approval of nivolumab with ipilimumab and chemotherapy.

Introduction

Lung cancer remains the leading cause of cancer deaths worldwide, despite recent reports of decreased mortality with advances in treatment (1, 2). In the U.S., approximately 229,000 adults will be diagnosed with lung cancer in 2020, of which approximately 80–84% of cases will be NSCLC (3). Most patients present with metastatic disease and long-term survival is poor (3). Metastatic NSCLC accounts for significant mortality globally, and effective and durable treatment options represent a significant unmet medical need.

In patients with metastatic NSCLC without targetable genomic tumor aberrations in EGFR, ALK, ROS1, or BRAF, standard-of-care first-line treatment options include immune checkpoint inhibitors administered in combination with four cycles of histology-based platinum-doublet chemotherapy (4–7). There are also several frontline chemotherapy sparing options for PD-L1-selected populations (8–13).

The approval of nivolumab, ipilimumab, and two cycles of platinum-doublet chemotherapy marked the first treatment regimen combining two immune checkpoint inhibitors for patients with advanced NSCLC, regardless of PD-L1 status. Importantly, the regimen includes only two cycles of chemotherapy compared to existing combinations of immune checkpoint inhibitors with four cycles of chemotherapy. Herein, we provide a summary of FDA’s review of the marketing application that led to the approval of nivolumab, ipilimumab, and chemotherapy for first-line treatment of advanced NSCLC. This review was conducted under Project Orbis, a global collaborative review program launched by FDA’s Oncology Center of Excellence (OCE) to facilitate concurrent submission, review, and regulatory action for high-impact clinically significant marketing applications across multiple participating countries (14).

Clinical Trials

The approval of nivolumab with ipilimumab in combination with platinum-doublet chemotherapy (nivo/ipi/chemo) was primarily based on CheckMate 9LA, an open-label trial in patients with metastatic or recurrent NSCLC without prior therapy for metastatic disease randomized 1:1 to nivolumab 360 mg IV every 3 weeks with ipilimumab 1 mg/kg IV every 6 weeks plus two cycles of histology-based platinum-doublet chemotherapy or four cycles of histology-based platinum-doublet chemotherapy. Patients with squamous histology received carboplatin IV AUC 6 plus paclitaxel IV 200 mg/m² every 3 weeks and patients with non-squamous histology received pemetrexed 500 mg/m² plus investigator’s choice of carboplatin AUC 5 or 6 or cisplatin 75 mg/m² every 3 weeks. Patients on the control arm with non-squamous histology could receive optional maintenance therapy with pemetrexed 500 mg/m² IV every 3 weeks until disease progression or unacceptable toxicity. The primary efficacy outcome measure was overall survival (OS). Progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review (BICR) were also hierarchically-tested as secondary endpoints.

Safety and efficacy data from CheckMate 568 and CheckMate 227 supported the approval of the CheckMate 9LA regimen. CheckMate 568 was a single-arm safety study in 36 patients with previously untreated metastatic or recurrent NSCLC treated with the same regimen evaluated in CheckMate 9LA. To determine contribution of components, data from the Checkmate 227 trial was also evaluated. CheckMate 227 was a large, randomized study containing multiple arms in two parts. Part 1 compared nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks to four cycles of platinum-doublet chemotherapy and Part 2 compared nivolumab 360 mg IV every 3 weeks plus four cycles of platinum-doublet chemotherapy to four cycles of platinum-doublet chemotherapy. The patient population in CheckMate 227 was similar to the patient population in CheckMate 9LA, enabling its use in establishing contribution of components.

Efficacy Results

The CheckMate 9LA trial randomized 719 patients to either nivolumab with ipilimumab plus chemotherapy, versus chemotherapy alone. Patients were stratified at randomization by PD-L1 levels (≥ 1% vs < 1% or non-quantifiable), histology (squamous vs non-squamous), and sex. At the pre-specified interim analysis, which was planned at 80% but occurred at an observed 87% of planned OS events, the median OS for nivo/ipi/chemo was statistically significant at 14.1 months (95% CI: 13.2, 16.2) versus 10.7 months (95% CI: 9.5, 12.5) for chemotherapy (hazard ratio [HR] 0.69; 96.71% CI: 0.55, 0.87; p = 0.0006) (Table 1). With an additional 4.6 months of follow-up and 81 additional OS events, the hazard ratio for OS was 0.66 (95% CI: 0.55, 0.80) and median OS was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% CI: 9.5, 12.6) for patients receiving nivo/ipi/chemo versus chemotherapy (Figure 1).

Table 1:

Efficacy Results – ITT population of CheckMate 9LA

	Nivolumab and Ipilimumab and Platinum-Doublet Chemotherapy N=361	Platinum-Doublet Chemotherapy N=358
OS
Deaths, n (%)	156 (43.2)	195 (54.5)
Median (months)a (95% CI)	14.1 (13.2, 16.2)	10.7 (9.5, 12.5)
Hazard ratio (96.71% CI)b	0.69 (0.55, 0.87)
Stratified log-rank p-valuec	0.0006
PFS per BICR
Disease Progression or Death, n (%)	232 (64.3)	249 (69.6)
Median (months)a (95% CI)	6.8 (5.6, 7.7)	5.0 (4.3, 5.6)
Hazard ratio (97.48% CI)b	0.70 (0.57, 0.86)
Stratified log-rank p-valued	0.0001
ORR per BICR
Responders, n (%)	136 (38)	90 (25)
(95% CI)e	(33, 43)	(21, 30)
Stratified CMH test p-valuef	0.0003
DOR per BICR
Median (months) (95% CI)a	10.0 (8.2, 13.0)	5.1 (4.3, 7.0)

Abbreviations: BICR, blinded independent central review; CMH, Cochran-Mantel-Haenszal; DOR, duration of response; ITT, intent-to-treat; ORR, overall response rate; OS, overall survival; PFS, progression-free survival

^aKaplan-Meier estimate.

^bBased on a stratified Cox proportional hazard model.

^cp-value is compared with the allocated alpha of 0.033 for this interim analysis.

^dp-value is compared with the allocated alpha of 0.0252 for this interim analysis.

^eConfidence interval based on the Clopper and Pearson Method.

^fp-value is compared with the allocated alpha of 0.025 for this interim analysis.

Source: OPDIVO (nivolumab) and YERVOY (ipilimumab) [package insert] (Ref. 29)

Figure 1: Overall Survival – CheckMate 9LA.

Source: OPDIVO (nivolumab) and YERVOY (ipilimumab) [package insert] (Ref. 29)

The observed survival advantage was supported by statistically significant improvements in both hierarchically tested secondary endpoints, BICR-assessed PFS followed by BICR-assessed ORR (Table 1). With 81% of the planned number of events for PFS, median PFS was 6.8 months (95% CI: 5.6, 7.7) in the nivo/ipi/chemo arm compared to 5.0 months (95% CI: 4.3, 5.6) for the chemotherapy arm, with a HR of 0.70 (97.48% CI: 0.57, 0.86). The ORR for nivo/ipi/chemo was 37.7% (95% CI: 32.7, 42.9) versus 25.1% (95% CI: 20.7, 30.0) for chemotherapy (p = 0.0003). Median duration of response (DOR) with nivo/ipi/chemo was 10.0 months (95% CI: 8.2, 13.0) compared to 5.1 months (95% CI: 4.3, 7.0) with chemotherapy.

Contribution of Components

To assess the contribution of effect of individual components within the CheckMate 9LA regimen, FDA evaluated the magnitude of effect and safety of the individual agents in the combination, as well as the totality of evidence available for the regimen. Each drug in the combination was supported by a strong biologic rationale, nonclinical characterization, and clinical evidence during the review of this regimen in CheckMate 9LA. Alternative approaches to traditional designs was necessary for efficient combination drug development, which included demonstration of activity from external randomized trials and/or monotherapy trials conducted in a similar disease setting.

FDA evaluated data from the randomized, controlled study CheckMate 227 using both within trial comparisons and non-formal cross trial comparisons (Table 2). Part 1 of CheckMate 227 demonstrated improved efficacy of the combination of nivo/ipi versus nivolumab monotherapy for the same patient population enrolled in CheckMate 9LA. In part 2 of CheckMate 227, although there was not a statistically significant improvement in overall survival, there was a positive trend favoring the combination of nivolumab with chemotherapy (nivo/chemo) over chemotherapy alone. In cross-trial comparisons, the magnitude of OS benefit over chemotherapy of the CheckMate 9LA regimen (nivo/ipi/chemo) was greater than that seen with either the nivo/ipi or nivo/chemo regimens in CheckMate 227. Finally, approvals of nivolumab plus ipilimumab in other tumor types, specifically melanoma, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and microsatellite instable-high or mismatch repair deficient colorectal cancer (MSI-H/dMMR CRC), were considered supportive evidence of the clinical benefit of the nivo/ipi combination.

Table 2:

Evaluation of Contribution of Components

	CheckMate 9LA*		CheckMate 227 Part 1†		CheckMate 227 Part 2ǂ
	Nivo+Ipi+Chemo N=361	Chemo N=358	Nivo+Ipi N=583	Chemo N=583	Nivo +Chemo N=377	Chemo N=378
Evaluation of Contribution of Components	Pivotal Trial		Contribution of two cycles of chemotherapy		Contribution of ipilimumab
Endpoints	OS, and PFS and ORR by BICR per RECIST v1.1		OS (ITT population)§		OS (ITT population)¥

Abbreviations: BICR, blinded independent central review; Chemo, chemotherapy; ITT, intent-to-treat; Ipi, ipilimumab; Nivo, nivolumab; ORR, Overall Response Rate; OS, Overall Survival; PFS, Progression-free Survival

^*Patients randomized to nivolumab 360 mg IV every 3 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for up to two years, plus two cycles of platinum-doublet chemotherapy; or, four cycles of platinum-doublet chemotherapy

^†Patients randomized to nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for up to two years; or, four cycles of platinum-doublet chemotherapy

^ǂPatients randomized to nivolumab 360 mg IV every 3 weeks for up to two years plus four cycles of platinum-doublet chemotherapy; or, four cycles of platinum-doublet chemotherapy

^§Data from CheckMate 227 combined for patients with both PD-L1-negative (<1%) and -positive (≥1%) tumors for evaluation of contribution of components within the CheckMate 9LA regimen (exploratory endpoint).

^¥Primary endpoint of OS in non-squamous NSCLC subgroup did not meet statistical significance, so secondary endpoint of OS in ITT population was not statistically tested.

Source: US FDA NDA/BLA Multi-disciplinary Review and Evaluation (sBLA 125554 and sBLA 125377) and Approval Package (Ref. 15)

Demographic variances between patient populations in CheckMate 227 and CheckMate 9LA were noted. In CheckMate 9LA, fewer patients were Asian, more patients had CNS metastases, and there were more current and former smokers. There were more patients with ECOG performance status 0 in CheckMate 227. Ultimately, these variations did not impact the broader conclusions drawn based on FDA analysis (15).

Safety Results

The safety review primarily focused on studies CheckMate 9LA and CheckMate 568, with additional relevant supportive data from CheckMate 227 and studies of nivolumab in combination with ipilimumab for other cancer types. In CheckMate 9LA, fatal adverse reactions (AR) occurred in seven (2.0%) patients treated with nivo/ipi/chemo and included hepatic toxicity (n=2), acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia (16). Permanent discontinuation due to ARs occurred in 24% of patients and serious adverse reactions (SARs) occurred in 57% of patients receiving nivo/ipi/chemo. For patients treated with nivo/ipi/chemo, 56% experienced dose delays or dose reductions. As expected, compared to chemotherapy alone, the nivo/ipi/chemo regimen had higher rates of diarrhea, rash, pruritus, and endocrinopathies which are known ARs associated with immune checkpoint inhibitors. Conversely, patients on the chemotherapy arm had higher rates of anemia. Key ARs of interest including myasthenic syndrome, demyelination, Guillain-Barre Syndrome, pancreatitis, uveitis, encephalitis, myocarditis, myositis, and rhabdomyolysis were infrequent or did not occur at all; only 1.4% and 0.6% of patients experienced any grade pancreatitis and encephalitis, respectively. The type, frequency, and severity of AR for nivo/ipi/chemo in CheckMate 568 were consistent with CheckMate 9LA.

The safety of nivo/ipi/chemo was also compared with safety data from nivo/ipi from CheckMate 227 Part 1 and nivo/chemo from CheckMate 227 Part 2. Fatal ARs, SARs, and ARs leading to permanent treatment discontinuation were similar between all three treatment regimens. However, the type of ARs differed and were reflective of the mechanism of action of the drugs in the regimens. ARs typical of immune checkpoint inhibitors, such as rash and diarrhea, occurred more frequently with nivo/ipi/chemo and nivo/ipi compared to nivo/chemo. ARs more common with chemotherapy, such as nausea and anemia, occurred more frequently with nivo/ipi/chemo and nivo/chemo compared to nivo/ipi. Overall, the safety profile of nivo/ipi/chemo in CheckMate 9LA was consistent with the known safety profiles of the individual components in the regimen and no new safety signals were identified.

Regulatory Insights

This approval of nivolumab with ipilimumab and two cycles of platinum-doublet chemotherapy for patients with metastatic or recurrent NSCLC adds to a growing number of available therapies. The CheckMate 9LA regimen is the first approval which combines an anti-PD-1 antibody with an anti-CTLA-4 antibody for advanced NSCLC in an unselected population, using only two cycles of chemotherapy.

The scientific rationale for combining nivolumab and ipilimumab is that they target distinct immune checkpoint proteins with complementary roles in regulating immune responses (17). Nivolumab is a monoclonal antibody against the PD-1 receptor on T cells and inhibits its interaction with PD-L1 on tumor cells. As tumors use PD-L1 expression to block anti-tumor T cell responses, PD-1 inhibition with nivolumab removes the blockade of pre-existing T cell responses. Ipilimumab is a monoclonal antibody against CTLA-4 and inhibition of CTLA-4 is associated with activating and recruiting novel T cells to tumors. It is hypothesized that CTLA-4 inhibition may be particularly valuable to induce de novo T cell responses in patients with tumors that do not express PD-L1 (18, 19). However, CTLA-4 inhibition has also been linked to compensatory increases in tumor PD-L1 expression which may explain why CTLA-4 inhibition, without PD-(L)1 inhibition, may have limited clinical benefit in NSCLC (19).

Several trials across tumor types, comparing immunotherapy-based, chemotherapy-sparing regimens to chemotherapy, have suggested the presence of a subgroup of patients with early mortality in the immunotherapy arm (20 – 23). It has been hypothesized that these patients have disease characteristics which may benefit from early cytoreductive chemotherapy, in combination with or followed by immunotherapy. The CheckMate 9LA regimen includes only two cycles of platinum doublet chemotherapy with concurrent nivolumab plus ipilimumab and eliminates the early survival deficit often observed in the absence of chemotherapy. These findings support the hypothesis that even a short course of cytotoxic chemotherapy, which acts on the tumor immediately, may bridge any potential delay in response to immune checkpoint inhibitors.

Although other combinations of anti-PD-(L)1 antibodies with platinum-doublet chemotherapy are already approved for the first-line treatment of metastatic NSCLC, CheckMate 9LA utilizes only two cycles of chemotherapy compared to four cycles of chemotherapy with the other regimens. Fewer cycles of chemotherapy may help reduce toxicity and the incidence of adverse events commonly associated with chemotherapy. For example, while cross-trial comparisons of adverse events are exploratory, there were higher rates of peripheral neuropathy and cytopenias for patients treated with four cycles of chemotherapy in combination with nivolumab (nivo/chemo) in CheckMate 227 Part 2 compared to patients treated with only two cycles of chemotherapy in the CheckMate 9LA regimen. While chemotherapy-associated toxicities may be reduced with this regimen compared to other combinations which include four cycles of chemotherapy, there is evidence of added toxicity due to ipilimumab. In cross-trial comparisons of regimens with and without ipilimumab, there were higher rates of diarrhea, rash, and pruritus in the ipilimumab-containing regimens.

The CheckMate 9LA study design did not isolate the contribution of components. The standard approach to developing combination drug regimens is to demonstrate contribution of components within a single randomized well-controlled trial which includes treatment arms of the individual drugs as single agents (24). However, to accelerate drug development in patients with cancer, some flexibility in trial design may be needed (24). The FDA review of contribution of components was supported with non-formal cross-trial comparisons with parts of CheckMate 227. Given lack of randomization, the use of comparisons to external trial data to determine contribution of components does not account for distribution of important prognostic factors. However, based on the biologic rationale supporting the immunotherapy combination, a clear improvement in OS in CheckMate 9LA, contribution of effect data from CheckMate 227, and demonstration of nivo/ipi efficacy in other solid tumors, contribution of components was adequately demonstrated.

The approval of nivo/ipi/chemo was the first NSCLC application, and the ninth application overall, to be conducted under Project Orbis, an FDA Oncology Center of Excellence (OCE) initiative established in 2019 to support concurrent submission and review of oncology drugs by multiple international health agencies (14, 25, 26). This program allowed for essential discussions among international health agencies regarding unique aspects of this drug application, such as the evaluation of the contribution of components, elimination of early mortality with the addition of chemotherapy to the combination, and overall safety of the multi-drug combination, to name a few. Discussions with Project Orbis Partners allowed for an increased understanding of the global regulatory landscape for NSCLC in terms of available therapies and practice patterns. This approval represents the first NSCLC regimen reviewed under Project Orbis, and the ninth overall ORBIS approval. Several previous publications detail the implementation strategy and experiences with this novel global regulatory program. (14, 25, 26)

The FDA also utilized the Real-Time Oncology Review (RTOR) and the Assessment Aid (AAid), to maximize efficiency of the drug review process (27, 28). Participating in Project Orbis did not cause any delays with the FDA review timeline and FDA approved this application two months ahead of schedule based on the Priority Review time clock. As a result of Project Orbis, the FDA and HSA approvals were coordinated to be near-simultaneous. The Australian TGA and Health Canada approvals occurred about six and 11 weeks following the US approval, respectively.

Conclusions

Nivolumab with ipilimumab in combination with two cycles of platinum-doublet chemotherapy is a new treatment option for patients with metastatic or recurrent NSCLC. Results from CheckMate 9LA demonstrate a favorable benefit-risk profile and support approval (Table 3). This approval marks the first regimen combining dual immune checkpoint blockade with chemotherapy for any tumor type, including lung cancer. The addition of limited chemotherapy cycles may reduce early mortality, however the addition of ipilimumab did increase toxicity. This was the first review of a lung cancer application conducted under Project Orbis and was approved two months ahead of FDA goal dates.

Table 3:

FDA benefit-risk analysis

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	● Lung cancer is the leading cause of cancer death in the US with poor long-term survival for metastatic disease. (1–3)	Metastatic NSCLC is a life-threatening condition.
Current Treatment Options	● FDA-approved treatment options for patients with metastatic NSCLC include:  ○ Combination platinum-based chemotherapy with pembrolizumab or atezolizumab  ○ In PD-L1 selected populations, there are several chemotherapy-sparing, immunotherapy options available	Combination of nivolumab plus ipilimumab and two cycles of chemotherapy (Nivo+Ipi+Chemo) provides another treatment option for patients with PD-L1-unselected NSCLC.
Benefit	In CheckMate 9LA ● HR for OS was 0.69 (96.71% CI: 0.55, 0.87; p-value 0.0006) favoring Nivo+Ipi+Chemo. ● Median OS for Nivo+Ipi+Chemo:  ○ 14.1 months (95% CI: 13.2, 16.2) ● Median OS for chemotherapy:  ○ 10.7 months (95% CI: 9.5, 12.5) ● HR for PFS: 0.70 (97.48% CI: 0.57, 0.86) favoring Nivo+Ipi+Chemo ● ORR and DOR were improved for Nivo+Ipi+Chemo compared to chemotherapy ● Contribution of components was assessed from cross-trial comparisons with data from CheckMate 227 (28)	● Evidence of effectiveness was supported by statistically significant improvements in  ○ OS  ○ PFS (BICR)  ○ ORR (BICR) and DOR This was in favor of Nivo+Ipi+Chemo compared to chemotherapy in CheckMate 9LA.
Risk and Risk Management	● Common (≥ 20%) adverse reactions (AR) due to any cause  ○ fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus. (28) ● Immune-mediated adverse reactions were similar to those previously described for the combination of nivolumab and ipilimumab. ● Identification and management of toxicities associated with nivolumab, ipilimumab, and chemotherapy are well-known.	● Safety profile is acceptable for treating a life-threatening disease. ● No new safety concerns were identified requiring risk management beyond labeling. ● Risk Evaluation and Mitigation Strategy (REMS) is not warranted.

Source: OPDIVO (nivolumab) and YERVOY (ipilimumab) [package insert] (Ref. 28)

US FDA NDA/BLA Multi-disciplinary Review and Evaluation (sBLA 125554 and sBLA 125377) and Approval Package (Ref. 15)