Sanborn Addresses Different Immunotherapies for ES-SCLC

Rachel E. Sanborn, MD

During a Targeted Oncology Case Based Peer Perspectives event, Rachel E. Sanborn, MD. the codirector of Thoracic Oncology Program, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute Providence Cancer Institute in Portland, OR, discussed the case of a 73-year-old woman with extensive-stage small cell lung cancer (ES-SCLC).

Targeted Oncology™: What are the recommended options from the National Comprehensive Cancer Network (NCCN) guidelines?

SANBORN: The updated NCCN guidelines, particularly after the recent FDA approvals, list the preferred regimens as carboplatin, etoposide, and atezolizumab [Tecentriq], followed by atezolizumab maintenance; then also options of either carboplatin or cisplatin with etoposide and durvalumab [Imfinzi], followed by durvalumab maintenance. For the next tier of categories, [the guidelines suggest] platinum doublets, or platinum chemotherapy and irinotecan doublets.¹

It’s certainly a lot more choices than we had in the past for patients with SCLC. Looking back 15 years ago, it was a little bit different. And I don’t think CAV [cyclophosphamide, doxorubicin, vincristine] would be a fair recommendation to have in there anymore.

Which data support the use of this regimen for this patient?

The IMpower133 study [NCT02763579] included patients with good performance status who were newly diagnosed. Now, this trial allowed for patients with treated brain metastases, but not de novo untreated brain metastases. [It] randomized to the reference regimen of carboplatin and etoposide; or carboplatin, etoposide, and atezolizumab; and then continuing atezolizumab until progression versus placebo.²

This demonstrated improvements, both in overall survival [OS] and progression-free survival [PFS], with atezolizumab. With the initial follow-up at 13.9 months, there was improvement in median OS from 10.3 months with placebo to 12.3 months with atezolizumab [HR, 0.70; 95% CI, 0.54-0.91; P = .007].

In the updated OS, [with] a follow-up at 22.9 months, the same numbers are observed.³ The numbers are consistent in that the median survival is still 10.3 for chemotherapy only and 12.3 for chemotherapy and atezolizumab. I think that the chemotherapy numbers are in line with what we would expect.

The 18-month OS rate improved from 21% to 34% [with placebo and atezolizumab, respectively].

Looking at subgroup analyses, it favored the combination with immunotherapy. The numbers for brain metastases, which are the ones that cross midline most profoundly, were a small number of patients [compared with] the total [35 out of 403], as you would expect, because patients had to have been stable enough from their newly diagnosed SCLC to first get brain radiation and then have stable disease, and wait to start systemic chemotherapy, which I don’t see often.

In terms of responders, there were better responses and more ongoing responses with the atezolizumab versus the placebo.

The adverse effects [AEs] were pretty much as expected—fairly well tolerated, in that there was not any significant difference in grade 5 toxicities.² In terms of grade 3 or 4 AEs, the toxicities were still related to the chemotherapy. There was a slightly higher rate of immune-related AEs with the patients getting atezolizumab versus the placebo.

What studies show the role of durvalumab this setting?

The CASPIAN study [NCT03043872], which was the randomized trial that allowed patients with asymptomatic, treated, or stable brain metastases, was more accepting with brain metastases [than IMpower133]. The reference regimen was platinum chemotherapy and etoposide, with optional prophylactic cranial irradiation afterward, versus chemotherapy and durvalumab, versus chemotherapy, durvalumab, and tremelimumab.⁴

The updated survival that was presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed that for the durvalumab and chemotherapy arm versus chemotherapy, there was a survival benefit seen with the median survival improving from 10.5 months to 12.9 months—close to what we saw from IMpower133 [HR, 0.75; 95% CI, 0.62-0.91; P = .0032]. The 18-month OS rate improved from about 25% to 32%.⁵

For the CASPIAN study, the subgroups all favored the combination with immunotherapy versus chemotherapy alone. The PFS looked fairly similar with this and with IMpower133. The PFS curves overlap through the first [6 months] before separating later within longer PFS and PFS benefit further out in the curves. More patients responded with the combination than with chemotherapy alone. Then there was longer duration of response with the combination.

The durvalumab and tremelimumab quadruplet combination versus the chemotherapy reference regimen did not show the same survival benefit. The median OS with the chemotherapy was 10.5 months, and with the quadruplet combination it was 10.4 months. Although the combination curve lands on top, the OS still does not come out as the advantage there.

The safety summarization among the 3 arms of the trial showed there were more grade 3/4 AEs with the durvalumab and tremelimumab arm, and relatively more serious AEs as well; also, a higher rate of patients with AEs leading to discontinuation, as well as more immune-related AEs. This may be why the outcomes don’t look the same as those [for] patients with durvalumab alone.

How do the atezolizumab and durvalumab regimens compare?

The IMpower133 regimen with atezolizumab and the durvalumab in the CASPIAN study had a median follow-up and number of patients [that] were similar. The control arm for IMpower133 was 4 cycles of carboplatin. The CASPIAN study allowed up to 6 cycles of either carboplatin or cisplatin. The OS looked close in both. Hazard ratios, PFS, and grade 3 AEs were also close.

What do you think of the patient’s case thus far?

The patient had constipation and nausea after the second cycle that were treated with supportive care. In terms of supportive care and follow-up, 2 cycles in, we’re going to presume the patient is responding.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 1.2021. Accessed August 17, 2020. https://bit.ly/2Q1HB6q}

_{2. Horn L, Mansfield AS, Szczęsna A, et al. 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}

_{3. Reck M, Liu SV, Mansfield 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}

_{4. Paz-Ares L, Dvorkin M, Chen Y, et al. 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}

_{5. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15):9002. doi:10.1200/ JCO.2020.38.15_suppl.9002}