NSCLC: Nivolumab plus low-dose ipilimumab used for first line therapy

Treatment with a combined immunotherapy of nivolumab plus low-dose ipilimumab prolonged overall survival compared to chemotherapy in previously untreated patients with advanced NSCLC regardless of PD-L1 expression of the tumor.

Extension of overall survival in advanced non-small cell lung cancer

Treatment with a combined immunotherapy of nivolumab plus low-dose ipilimumab prolonged overall survival compared to chemotherapy in previously untreated patients with advanced non-small cell lung cancer (NSCLC) regardless of PD-L1 expression of the tumor.

The findings were shown in part 1 of the CheckMate-227 study presented by Solange Peters, Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) at the Presidential Symposium at the ESMO Congress 2019 in Barcelona and published in parallel in the New England Journal of Medicine1,2.

The two immunotherapeutic agents nivolumab and ipilimumab have different but complementary mechanisms of action. The CTLA-4 inhibitor ipilimumab induces de novo anti-tumor reactions of T cells, while the PD-1 inhibitor nivolumab restores and enhances anti-tumour T cell function. This is the rationale behind the combination of the two substances. It had already led to an improvement in overall survival in Phase 3 studies in renal cell carcinoma and melanoma.

The CheckMate-227 open randomized phase-3 study, funded by BMS and Ono, looked into how nivolumab and nivolumab-based regimens compared to chemotherapy in first-line advanced NSCLC.

1,189 patients with stage-IV NSCLC and PD-L1 expression ≥ 1% received randomized nivolumab plus ipilimumab, nivolumab alone or chemotherapy. 550 patients with PD-L1 expression ≤ 1% received nivolumab plus ipilimumab, nivolumab plus chemotherapy or chemotherapy. The study had two coprimary endpoints, progression-free survival (PFS) and overall survival (OS). The results on PFS had already been published in the NEJM in 2018. Peters now presented the overall survival results in patients with PD-L1 expression ≥ 1% from the comparison of nivolumab plus ipilimumab (n = 396) and chemotherapy (n = 397).

Immunotherapy prolongs overall survival

After a follow-up period of 29.3 months, the median overall survival was 17.1 months in the nivolumab/ipilimumab group and 14.9 months in the chemotherapy group. This means a significant reduction of the mortality risk by a relative 29% (hazard ratio 0.79, p = 0.007). After two years, 40% were still alive in the immunotherapy group and 33% in the chemotherapy group.

35.9% of the patients responded to immunotherapy and 30.0% to chemotherapy. The median response time was 23.2 months with immunotherapy and 6.2 months with chemotherapy. For patients with a high PD-L1 expression ≥ 50%, the response rate was 44.4% for immunotherapy and 35.4% for chemotherapy. The median overall survival was 21.2 and 14.0 months, respectively.

However, immunotherapy was also effective in PD-L1 expression < 1%: median overall survival was 17.2 months compared to 12.2 months under chemotherapy (HR 0.62). After 2 years, 40% of the patients were still alive under immunotherapy and 23% under chemotherapy. Patients with nivolumab and chemotherapy (n = 177) survived a median of 15.2 months (HR 0.78). The response rates of patients with low PD-L1 expression were 27.3% for nivolumab/ipilimumab, 37.9% for nivolumab/chemotherapy, and 23.1% for chemotherapy. The median response was 18.0 months, 8.3 months, and 4.8 months, respectively.

An evaluation of all patients, regardless of the extent of PD-L1 expression, showed that they survived 17.1 months median with nivolumab/ipilimumab (n = 583) and 13.9 months median with chemotherapy (n = 583) (HR 0.73). The effects of nivolumab/ipilimumab were demonstrated in all subgroups. No previously unknown adverse effects were observed.

Peters summarized:

Many questions still open

Discussant Sanjay Popat, from the Royal Marsden Hospital in London, pointed out, however, that the immune combination therapy is associated with considerable toxicity, and in about one-third of the patients there were Grade 3/4 side effects.

A nivolumab monotherapy with a PD-L1 expression ≥ 1% has only a limited effect in the first-line therapy, ipilimumab increases the effect, but at the expense of tolerability. With a PD-L-1 expression below 1%, the immunotherapy combination is more effective than chemotherapy, but this is only an exploratory analysis.

In patients with a PD-L1 expression ≥ 1%, the effect of the immunotherapy combination on overall survival was better than the effect of chemotherapy, but this was mainly due to the high efficacy in patients with strong PD-L1 expression over 50%. Surprisingly, no significant effect was observed in patients with PD-L1 expression between 1 and 49%. Many questions are still open, which must be clarified in further research, such as the optimal dosage, the duration, and the scheme of the ipilimumab therapy. It is also unclear whether nivolumab is the right partner for ipilimumab.

1. Peters S. Nivolumab + low-dose ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer (NSCLC): CheckMate 227 Part 1 final analysis. ESMO 2019 Annual Meeting, 27. September until 1. October 2019, Barcelona, LBA4.
2. Hellmann M et al. Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer. N Engl J Med, published online on 28. September 2019