Comparing Immunochemotherapy Combinations in Patients With ES-SCLC

Jun Zhang, MD, PhD

Jun Zhang, MD, PhD, associate professor, University of Kansas Medical Center, reviews the preferred treatment options for extensive-stage small cell lung cancer (ES-SCLC) in a 73-year-old patient during a Targeted Oncology Case Based Peer Perspective event.

Targeted Oncology: How has the treatment landscape for these patients changed?

ZHANG: The treatment of ES-SCLC is quite different from decades ago. Because of immunotherapy, now we are able to prolong—at least in the statistical definition—overall survival [OS]. Immunotherapy is now considered as one of the important additions of chemotherapy for patients with ES-SCLC.

What are the preferred therapies in this setting, according to the National Comprehensive Cancer Network (NCCN) guidelines?

We have different options at this moment, and the preferred [option] is immunotherapy plus chemotherapy. We have a choice of atezolizumab [Tecentriq] and durvalumab [Imfinzi] at the moment. Atezolizumab was approved by the FDA last year in March, and durvalumab was approved this year in March.^1,2

Which data support the use of atezolizumab and chemotherapy in this patient?

The phase 3 IMpower133 trial [NCT02763579] [had] 2 arms.³ One arm was the conventional carboplatin/etoposide. It only allowed carboplatin here, not cisplatin—that’s a difference from the CASPIAN [NCT03043872] trial. In the other arm, in addition to chemotherapy, [the investigators] added atezolizumab. The chemotherapy was only allowed for 4 cycles in the IMpower133 study. The coprimary end points were both the OS and the progression-free survival [PFS].

These data showed…with additional atezolizumab in addition to carboplatin/etoposide, the median survival was 12.3 months versus 10.3 months [HR, 0.70; 95% CI, 0.54-0.91; P = .007], [an additional] 2 months’ OS benefit. For PFS, there was about a 0.9-month [difference] and a ratio [that was] significant [HR, 0.77; 95% CI, 0.62-0.96; P = .02].

How did the updated efficacy compare?

The updated OS benefit basically carried the same benefit.⁴ The median OS was again 12.3 months with addition of atezolizumab compared with conventional chemotherapy at 10.3 months [HR, 0.76; 95% CI, 0.60-0.95; P = .0154].

The group analysis showed that patients who had brain metastases didn’t respond and derive much benefit, suggesting that this is an unmet need for patients with metastatic disease and the brain metastases. It seems we need to have more innovative therapies for this group of patients.

The response rates were roughly similar, but patients with ongoing response at 2 years’ follow-up with the addition of atezolizumab was 9.1% versus 2.3%.

Grade 3 and 4 adverse events [AEs], with and without immunotherapy, [were] comparable; but diarrhea seemed to get [worse] with the patients on atezolizumab.³ [Investigators] have a good summary that shows that the immune rate of AEs in the atezolizumab group is almost double compared with the placebo group.

What other options are available in this setting, and which trials are associated with these options?

The CASPIAN trial had 3 arms.5 The fi rst arm was the chemotherapy, and here [they used] either carboplatin or cisplatin, up to 6 cycles. In fact, the patient was also allowed to have prophylactic cranial irradiation [PCI]. The second arm was durvalumab with chemotherapy. The third arm was durvalumab, chemotherapy, and the anti-CTLA-4 tremelimumab. The data were updated in the 2020 American Society of Clinical Oncology Virtual Scientific Program.⁶

The primary end point was OS. The updated median OS for the patients [receiving only] durvalumab achieved 12.9 months and, if I remember correctly, this is probably the longest in history for ES-SCLC. The hazard ratio was 0.75, meaning about 25% death reduction [95% CI, 0.62-0.91; P = .0032]. The hazard ratio and the P value were significant.

The updated subgroup analysis [was] interesting [because] in [the] original paper last year, published in Lancet Oncology, there was not much significant benefit if the patient receives cisplatin. Now I think the updated data suggest, for both carboplatin and cisplatin, there is benefit [with] the addition of durvalumab.^5,6 It [also] showed that a patient who had brain metastases seemed [as though they were] not deriving much benefit. I think this is an unmet need, especially with our expertise in radiation oncology, to see whether we can do something to benefit this group of patients.

The updated PFS value, when you look at the number numerically, seemed to be similar between these 2 arms. But when you look at the timeline, for example at 24 months with the addition of durvalumab, the probability of survival was 11% versus only 2.9% in the control arm.⁶

Different from the IMpower133, the benefit of the increase of overall response rate with the combination was 67.9% versus 58% [95% CI, 1.08-2.18].

What did adding tremelimumab do to affect the responses to the combination for patients on the CASPIAN trial?

There was a long-waiting result to see whether the addition of anti-CTLA-4 can further increase the benefit of immunotherapy. Unfortunately, there was no survival benefit. The numerical number was similar [10.4 with tremelimumab vs 10.5 with chemotherapy], and also the prespecified P value was not met [P = .0451]. So, this was a negative study, suggesting that the addition of anti-CTLA4 has no extra benefit.

This is reminiscent of the prior study that I think was published by Martin Reck, MD, 3 or 4 years ago, using only anti-CTLA-4 with platinum chemotherapy and etoposide.⁷ It was published in the Journal of Clinical Oncology and did not show the benefit of anti-CTLA4. So, I think, based on these 2 studies, we can say that there is not much value of adding anti-CTLA-4 for patients with ES-SCLC.

More importantly, with the addition of anti-CTLA4, not only did we not see the survival benefit but, at the same time, there were more AEs. For example, the grade 3 and 4 AEs were much higher in the tremelimumab group, and the immune-mediated AEs were much higher. Also, the AEs leading to death [were] 10.2% in the quadruplet group compared with [4.9% in the] durvalumab-only group.

How would you compare the IMpower133 and CASPIAN data?

In the IMpower133 study, the control arm was up to 4 cycles of chemotherapy with carboplatin, and in CASPIAN you were allowed to have up to 6 cycles and you [had] the freedom to choose carboplatin versus cisplatin.^3,5 Also, PCI was allowed in the CASPIAN study.

The OS [for the combination arm of both trials] was significant; PFS [for both trials] was significant.4,6 Overall response was higher in CASPIAN study [for the combination arms]. When you look at the immune-mediated toxicities, they seem much lower in CASPIAN, especially in the control group. I guess one of the reasons was because CASPIAN was open-label. It’s easier for the investigator to identify which are immunemediated toxicities.

When we’re talking about immunotherapy, we have to focus on not only the response but also the toxicities as well. But I think we have to interpret the data cautiously. The studies are designed a different way. IMpower133 was double-blinded, whereas CASPIAN was open-label, so people know which arm is receiving durvalumab versus placebo. This was probably one of the reasons that we see much lower immune-related AEs, because if you know that the patient is only receiving chemotherapy, then you’ll probably attribute all those AEs to chemotherapy instead of immune-mediated process. I think we have to interpret data a bit cautiously about that.

This is definitely a good point, that we have to focus on toxicity as well.

Design-wise, there were some advantages to CASPIAN: 6 cycles, cisplatin allowed, and PCI [allowed]. But I think they are largely interchangeable.

What do you view as the most critical unmet needs for patients with ES-SCLC?

In my opinion, as I mentioned in both studies, the patients with the brain metastases seem to [have minimal] benefit from this combination. So if at a certain point we need to take advantage of radiation therapy, this is something that I would like to know.

There are some interesting data showing that, for example, patients with intact OB1 versus mutant OB1—about 80% of patients with SCLC have an OB1 mutation—but for those with OB1 intact, it seems [as though] there is enhanced response to CDK4/6 inhibitors, and there are some studies ongoing. So, hopefully, we can have some interesting data from them.

_References:

_{1. FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA. Updated March 19. 2019. Accessed November 1, 2020. https://bit.ly/34Nj64Y}

_{2. FDA approves durvalumab for extensive-stage small cell lung cancer. Updated March 30. 2020. Accessed November 1, 2020. https://bit.ly/2JtOgq2}

_{3. Horn L, Mansfi eld AS, Szczesna A, et al; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064}

_{4. Reck M, Liu SV, Mansfi eld AS, et al. IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann Oncol. 2019;30(suppl 5):v710-v717. doi:10.1093/annonc/mdz264}

_{5. Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6}

_{6. Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from thephase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15):9002. doi:10.1200/ JCO.2020.38.15_suppl.9002}

_{7. Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensivestage small-cell lung cancer. J Clin Oncol. 2016;34(31):3740-3748. doi:10.1200/JCO.2016.67.6601}