Immunotherapy in SCLC: trial data

The treatment of SCLC has not changed in recent years. “We are still treating these patients with platinum plus etoposide as first-line therapy”, Dr Enriqueta Felip (Vall d’Hebron University Hospital, Spain) said. “In second line, only topotecan has been approved.” The combination of chemotherapy and immunotherapy seems the most promising option. In the first-line setting, chemotherapy and atezolizumab resulted in a modest improvement of OS but long-term follow-up data is needed. Results in the second line and maintenance setting are disappointing.

The randomised, phase 3 CA184-156 trial, evaluating platinum/etoposide plus ipilimumab or placebo as first-line treatment of extensive disease (ED)-SCLC patients, showed no signal of efficacy with the addition of ipilimumab. Toxicity, mainly diarrhoea and rash, and discontinuation rate (18% vs 2%) were significantly higher in the ipilimumab arm [1]. “So, this was a negative study”, Dr Felip concluded.

More recently, the phase 1/2 Checkmate 032 trial evaluated nivolumab with or without ipilimumab in pretreated ED-SCLC patients, who were not selected for PD-L1 expression. The participants were previously treated with platinum-based therapy [2]. “The response rate in the non-randomised cohort was 11% with nivolumab and 23% with nivolumab plus ipilimumab”, Dr Felip said. “In the randomised cohort, the results were comparable (response rates of 12% and 21%, respectively).” Furthermore, the investigators analysed PD-L1 expression, which was found to be low compared with observations in NSCLC. The outcomes were similar regardless of PD-L1 expression. The 2-year survival for patients treated with nivolumab plus ipilimumab was 26% and for those treated with nivolumab was 14%. The combination therapy was associated with a higher rate of treatment-related adverse events, mainly during week 1 and 2, but also during week 3 and 4.

With respect to the first-line treatment of SCLC, Dr Felip summed up some trials which are ongoing or have been presented or published recently. The IMpower-133 showed a survival benefit of etoposide/cisplatin chemotherapy plus atezolizumab compared with placebo (median OS 12.3 vs 10.3 months, respectively; HR for death, 0.70; P=0.007; median PFS 5.2 vs 4.3 months, respectively; HR for disease progression or death, 0.77; P=0.02) [3]. “So, this study is positive for the main endpoint”, Dr Felip stated. “We are awaiting the results of the Keynote-604 and CASPIAN trials, which are evaluating pembrolizumab and durvalumab with or without tremelimumab, respectively, in addition to the same chemotherapeutic backbone.”

In second-line setting, the global, open-label, phase 3 CheckMate-331 trial compared nivolumab with standard chemotherapy in ED-SCLC patients, who relapsed or progressed after first-line therapy. “This was again a negative trial”, Dr Felip concluded. Namely, no statistically significant improvement in OS was seen with nivolumab compared to chemotherapy (median OS: 7.5 vs 8.4 months, respectively; HR 0.86) [4]. “Potentially, a subset of patients benefits from this treatment strategy, but we have to identify in which patients that is the case.”

The phase 3 CheckMate-451 trial was a maintenance study, in which ED-SCLC patients with response to first-line chemotherapy subsequently received either nivolumab or ipilimumab plus nivolumab or placebo. The results were presented during the ELCC meeting. After a minimum follow-up period of 9 months, OS was not significantly prolonged with nivolumab plus ipilimumab vs placebo (HR 0.92; P=0.3693) [5]. “Again, this is a negative trial.”

Future immunotherapeutic agents and strategies

There are 2 novel immunotherapeutic agents targeting DLL3 in development for the treatment of SCLC: AMG757 and AMG119. AMG757 is a half-life extended bispecific T cell engager (BiTE®) antibody construct. AMG119 is an adoptive chimeric antigen receptor (CAR) T cell therapy. For potential future use, it is possible to combine immunotherapy with other strategies, which are targeting other pathways, for example:

• targeting DNA damage and repair with PARP1 inhibition;
• targeting cell cycle abnormalities with WEE1 and aurora kinase A inhibitors;
• targeting developmental regulatory pathways with DLL3 and Notch inhibitors; and
• targeting epigenetics with EZH2-targeted siRNA.

1. Von Pawel J, et al. J Clin Oncol. 2013;31(15_suppl):TPS7608.
2. Antonia SJ, et al. Lancet Oncol. 2016;17:883-895.
3. Horn L, et al. N Engl J Med 2018;379:2220-9.
4. Reck M, et al. ESMO I-O 2018, Abstract LBA3.
5. Owonikoko T, et al. Ann Oncol. 2019;30(Suppl 2):LBA-1_PR.

Posted on 25 June, 201915 March, 2021