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Nivolumab ± Ipilimumab in Advanced SCLC
Immunotherapy: An Intriguing Work in Progress for the Treatment of Advanced SCLC
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New treatments for advanced (extensive stage) small-cell lung cancer (SCLC) have been in short supply for decades. The last major paradigm shifts occurred in 1998 and 2007 when the FDA approved intravenous and oral topotecan, respectively, for second-line treatment of platinum-sensitive SCLC. Although no new FDA approvals have yet been granted, there is a new therapeutic approach gaining traction in advanced SCLC: immunotherapy with the PD-1 inhibitor nivolumab, alone or in combination with the CTLA-4 inhibitor ipilimumab, is now guideline recommended based on data from the phase I/II CheckMate 032 trial.

CheckMate 032: Nivolumab With or Without Ipilimumab in Advanced SCLC
Patients with advanced SCLC treated with at least 1 previous platinum-based regimen were enrolled on CheckMate 032, initially in a nonrandomized sequential fashion followed by a randomized fashion (Figure). The primary endpoint was ORR by investigator assessment.

Figure. CheckMate 032 trial design.

An interim analysis of the nonrandomized cohort reported numerically higher ORRs with the combination of nivolumab plus ipilimumab vs nivolumab alone, including in both platinum-sensitive and platinum-resistant patients: 23% with nivo 1/ipi 3 and 19% with nivo 3/ipi 1 vs 10% with nivolumab monotherapy. No statistical comparisons were made and the 95% CIs for the ORRs of all 3 groups overlapped. The median durations of response for nivo 1/ipi 3, nivo 3/ipi 1, and nivolumab monotherapy were 7.7 months, 4.4 months, and not reached; median PFS was 2.6, 1.4, and 1.4 months; and median OS was 7.7, 6.0, and 4.4 months. There was also a numerically higher rate of grade 3/4 treatment-related adverse events (AEs) with combination therapy vs nivolumab monotherapy: 30% with nivo 1/ipi 3 and 19% with nivo 3/ipi 1 vs 13% with nivolumab monotherapy. Similar results were observed with extended follow-up of the nonrandomized cohort and for the randomized cohort, although full data on the randomized cohort have not yet been presented. Overall, 4 treatment-related deaths occurred with combination therapy (myasthenia gravis, pneumonitis, seizures/encephalitis, autoimmune hepatitis) vs 1 with nivolumab monotherapy (pneumonitis).

The data from CheckMate 032 suggest the following: 1) Although some SCLCs are immunotherapy sensitive, the modest efficacy rates indicate that most are not; 2) despite some hints, it is still not completely clear that combination immunotherapy with CTLA-4 and PD-1 inhibition is any more effective than PD-1 inhibition alone; and 3) certain unusual immunotherapy AEs such as encephalitis could be more prominent in SCLC, perhaps due to known paraneoplastic autoimmunities that can occur in this population. To further understand immunotherapy’s role in SCLC, we need larger, more robust phase III trials, but determining which doses/combinations to further evaluate presents a major challenge.

Choice of Nivolumab Plus Ipilimumab Dose to Further Evaluate in SCLC
A 30% severe toxicity rate has traditionally been considered acceptable when selecting a chemotherapy dose/regimen for advanced cancers. Based on the results for the nonrandomized cohort of CheckMate 032, where nivo 1/ipi 3 had the numerically highest ORR with a grade 3/4 treatment-related AE rate of 30%, it makes sense that this combination regimen was chosen for further exploration in the ongoing phase III CheckMate 451 trial. It is also the licensed regimen in melanoma.

However, the tolerability of nivo 1/ipi 3 has varied markedly between studies of different tumor types. In CheckMate 016, first-line nivo 3/ipi 1 was better tolerated than nivo 1/ipi 3 among patients with renal cell carcinoma (RCC) as reflected in grade 3/4 treatment-related AE rates of 38% vs 62%, respectively. Furthermore, in CheckMate 012, neither regimen was considered tolerable in patients with newly diagnosed non-small-cell lung cancer (NSCLC), with 58% and 44% of patients experiencing grade 3/4 treatment-related AEs on nivo 1/ipi 3 and nivo 3/ipi 1, respectively.

Given that patients with SCLC are traditionally considered to represent a less-fit population, it is curious that immunotherapy tolerability appears better for patients with SCLC than those with RCC or NSCLC. Perhaps previous cytotoxic chemotherapy in CheckMate 032 blunted some of the immune-mediated toxicities in patients with SCLC, whereas patients with RCC or NSCLC in the other studies were cytotoxic naive. Alternatively, in the race to be the first licensed immunotherapy combination across multiple tumor types, there is a concern that regimens/doses are being chosen on the basis of what could be random fluctuations in toxicity and efficacy derived from small, underpowered studies. As our understanding of predictive factors for immunotherapy benefit or toxicity is still in its infancy, relevant imbalances in sensitivity populations could easily exist between different cohorts.

PD-L1 as a Biomarker of Immunotherapy Benefit in SCLC
Although PD-L1 expression has some predictive role for immunotherapy benefit in NSCLC, its role in SCLC remains debatable. In the nonrandomized cohort of CheckMate 032, only 18% of evaluable SCLC patients were PD-L1 positive at any level. Furthermore, ORR was numerically higher among patients with PD-L1 < 1% vs PD-L1 ≥ 1% for both combination therapy (32% vs 10%) and nivolumab monotherapy (14% vs 9%). By contrast, in an updated analysis of the phase Ib KEYNOTE-028 trial of pembrolizumab monotherapy in 24 patients with SCLC deemed to be PD-L1 ≥ 1%, the response rate was 38%, possibly suggesting some benefit from PD-L1 enrichment.

Nivolumab Monotherapy vs Nivolumab Plus Ipilimumab Combination Therapy in SCLC
To date, guidelines on SCLC have avoided specific recommendations on second-line PD-1/CTLA-4 inhibitor combination therapy vs PD-1 inhibitor monotherapy, as well as a preferred dose/regimen or the need for PD-L1 preselection. Although immunotherapy is clearly beneficial in some patients with SCLC, I believe it should still be used with caution until we see the detailed results of larger randomized studies such as CheckMate 451.

Do you use immunotherapy for your patients with SCLC? Please leave a comment below.

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