Dual immunotherapy with nivolumab and ipilimumab represents a potential new first-line treatment option for patients with advanced non-small cell lung cancer

The CheckMate 227 trial was the first phase III trial to assess the efficacy of nivolumab plus ipilimumab as compared to chemotherapy in the first-line for patients with advanced non-small cell lung cancer. Compared to platinum-based chemotherapy, the immunotherapy combination resulted in a clinically meaningful overall survival improvement, regardless of PD-L1 expression, with deep and durable responses and without any new toxicities. As such, the dual immunotherapy combination of nivolumab plus ipilimumab represents a new chemotherapy-free treatment option for patients with first-line advanced non-small cell lung cancer.

Introduction

Whereas the CTLA4 inhibitor ipilimumab is able to induce de novo anti-tumour T-cell responses, the PD-1 inhibitor nivolumab enhances a pre-existing T-cell response leading to a restored anti-tumour T-cell function. As such, both agents have a distinct mode of action and a potential synergistic activity. The latter was already confirmed in the treatment of renal-cell carcinoma and melanoma where the combination of nivolumab plus ipilimumab (NIVO + IPI) demonstrated impressive clinical activity. At ESMO 2019, similar results were presented in patients with non-small cell lung cancer (NSCLC).

Methods

In the CheckMate 227 study, chemotherapy-naïve patients with stage IV or recurrent NSCLC without EGFR or known ALK alterations, were randomized (1:1:1) to receive nivolumab (3 mg/kg Q2W) plus ipilimumab (1 mg/kg Q6W), nivolumab 360 mg (Q3W) (plus chemotherapy in patients with <1% PD-L1 expression), or chemotherapy alone. The median age of the patients in all subgroups was 64 years and about one third of the patients were female. Patients did not receive prior systemic therapy and were not treated for CNS metastases. All patients had an ECOG performance status of 0 or 1. Patients were stratified by histology and were treated until disease progression, unacceptable toxicity or for two years of immunotherapy. The primary endpoint was the overall survival (OS) for NIVO + IPI versus chemotherapy in the subgroup patients with PD-L1 expression in at least 1% of tumour cells. Secondary endpoints were progression-free survival (PFS) and OS of nivolumab plus chemotherapy versus chemotherapy alone in patients with PD-L1 < 1% and OS of nivolumab versus chemotherapy in patients with PD-L1 ≥ 50%.

Results

In patients with a PD-L1 ≥ 1% (part 1a of the study design), the OS increased from 14.9 months in patients on chemotherapy to 17.1 months in patients who were treated with NIVO + IPI (HR 0.79 [97.72% CI: 0.65-0.96]; p<0.007). Patients on nivolumab monotherapy had a median OS of 15.7 months. The 12-month OS rate for NIVO + IPI was 63%, as compared to 56% in the chemotherapy arm. At 24 months, these rates were 40% and 33% respectively. The median PFS by blinded independent central review (BICR) in this subgroup was 5.1 months in the NIVO + IPI arm, as compared to 4.2 months in the chemotherapy arm. The ORR by BICR was 35.9% in the NIVO + IPI arm as compared to 27.5% in the NIVO arm and 30.0% with chemotherapy. The corresponding median duration of response (DoR) was 23.2 months for patients treated with NIVO + IPI, 15.5 months for patients on NIVO and only 6.2 months for patients in the chemotherapy group. In patients with a PD-L1 ≥ 50%, ORR rates were 44.4%, 36.9% and 35.4% for NIVO + IPI, NIVO and chemotherapy groups, respectively. Median DoR with NIVO + IPI, NIVO and chemotherapy was 31.8, 17.5 and 5.8 months, respectively.

In patients with a PD-L1 expression of < 1% (part 1b of the study design), the median OS with NIVO + IPI was 17.2 months, as compared to 15.2 months with NIVO + chemotherapy and 12.2 months in the chemotherapy arm. At 12 months, this corresponds to an OS rate of 60%, 59% and 51% with NIVO + IPI, NIVO + chemotherapy and chemotherapy, respectively. At 24 months, the survival benefit of NIVO + IPI was even more pronounced with 40% of patients still being alive as compared to 35% and 23% for NIVO + chemotherapy and chemotherapy, respectively. In this patient population, 25.1% of the patients achieved a partial or complete response on NIVO + IPI, as assessed by BICR, as compared to 36.2% and 22.0% for patients receiving NIVO + chemotherapy and chemotherapy monotherapy. Patients in the NIVO + IPI arm achieved a median DoR of 18.0 months. For patients receiving NIVO + chemotherapy and patients on chemotherapy, this was only 8.3 and 4.8 months, respectively.

Overall (part 1a +1b), NIVO + IPI invoked a median OS benefit of 3.2 months (HR 0.73 [95% CI: 0.64-0.84]). The OS rates at one year were 62% for patients receiving NIVO + IPI and 54% for patients on chemotherapy. At 24 months, 40% of the patients on NIVO + IPI treatment were still alive, as compared to only 30% of the patients on chemotherapy. No consistent correlation was observed between survival outcomes with NIVO + IPI versus chemotherapy and the patient’s PD-L1 status. No new toxicities were observed and the most frequent adverse events of any grade were diarrhoea (17%), rash (17%), fatigue (14%), and decreased appetite (13%).

Conclusions

In summary, CheckMate 227 was the first phase III study demonstrating the efficacy of combined PD-1 and CTLA4 inhibition in metastatic NSCLC. The trial met its primary endpoint by demonstrating a significant OS benefit with the immunotherapy combination over chemotherapy in patients with PD-L1 ≥1%. A clinically meaningful OS improvement was observed regardless of PD-L1 expression, with deep and durable responses. The addition of IPI to NIVO improved outcomes, both compared to NIVO monotherapy in PD-L1 ≥ 1% patients and compared to NIVO + chemotherapy in PD-L1 < 1%. No new safety signals were observed for NIVO + low dose IPI.  The combination of NIVO + IPI therefore represents a potential new first-line treatment option for patients with advanced NSCLC.

Reference

Peters S, Ramalingam S, Paz-Ares L, et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) vs platinum-doublet chemotherapy (chemo) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): CheckMate 227 part 1 final analysis. Presented at ESMO 2019; Abstract LBA4.