Next step in SCLC: immunotherapy combinations
The phase 3 trial IMpower133 (NCT02763579), which looked at aezolizumab (Tecentriq) plus platinum-based chemotherapy and etoposide in patients with untreated extended stage small cell lung cancer ( ES-SCLC) has helped lay the groundwork for the exploration of other new combinations of immunotherapy. , according to Ravi Salgia, MD, PhD.
In the Phase 3 CASPIAN trial (NCT03043872), researchers examined the use of first-line durvalumab (Imfinzi) plus the same chemotherapy backbone in patients with ES-SCLC.1 The combination resulted in a lasting improvement in overall survival, but the addition of tremelimumab (formerly ticilimumab; CP-675,206) did not appear to induce any further statistically significant improvement.
Now, a Phase 1 study (NCT04560972) will build further on the IMpower133 regimen by examining the safety of the new agent LB-100 in combination with carboplatin, etoposide and arezolizumab in patients with SE- Untreated SCLC.2 Further exploration of immunotherapy regimens will be needed, Salgia said.
“It is important for us to realize that the burden of tumor mutations for SCLC is very high,” said Salgia. “We need to be able to [consider whether] immunotherapy [may] works even better [when used] in combination with chemotherapy or other therapeutic strategies. “
In an interview with Oncology Nursing News‘sister publication, OncLive® During a webinar on Lung Cancer, An Institutional Cancer Perspective, Salgia, medical oncologist and Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope, discussed pivotal trials that have rocked the Small cell lung cancer treatment paradigm, new immunotherapy regimens under investigation and next steps in research.
OncLive®: What is your approach to select the treatment of patients with limited-stage SCLC [LS-SCLC] vs ES-SCLC?
Salgia: SCLC is a difficult disease to treat. We have come a long way in terms of thinking about [the disease] and we know that there are 2 varieties of [the disease] that we consider in terms of staging: LS-SCLC and ES-SCLC. For [patients with] LS-SCLC, we [administer] chemotherapy and radiotherapy [with consideration] for prophylactic cranial radiation. For those who have [ES-SCLC], we are changing the paradigm. Currently we use chemotherapy with immunotherapy. After the failure of the first line of treatment, [we have a] second line option, which is lurbinectin [Zepzelca]. Of course we really try to point out [enrollment to] clinical trials as well.
Starting at the first line, how do you apply the results of the pivotal phase 3 IMpower133 trial to clinical practice?
The results have [demonstrated] than platinum-based chemotherapy with etoposide in combination with aitzolizumab [yield] better survival. It’s revolutionary for us and we use it [agent] in our clinical practice. It is important to understand that the seriousness of the side effects was not worse than [what was reported in] the chemotherapy arm.
An ongoing study that is open in City of Hope builds on the success observed with the IMpower133 diet. Could you highlight this research and its potential implications?
For ES-SCLC, we use carboplatin and etoposide with aitzolizumab, as an example. However, we do know that patients can relapse and relapse, so we wanted to improve that. In our lab, we discovered that the PP2A pathway in SCLC is very important. We can inhibit this pathway with a drug called LB-100. We use a backbone from the IMpower133 diet – carboplatin and etoposide with aitzolizumab – and combine it with LB-100. We will publish [these data] relatively soon. It is important to realize that this is a Phase 1 study, but we are optimistic that this [research] will [result in] revolutionary breakthroughs.
Does LB-100 have a safety profile that makes it suitable for use in a 4-drug combination?
The initial LB-100 study [that examined the] drugs alone were taken here in City of Hope, and that [research] was published by Vincent Chung, MD, and colleagues. The security profile [of LB-100] was really good. [However], we do not know yet [what this will look like] in combination [with other agents] because this is a phase 1 study. Once we start the study, we really hope the toxicity is no different from that [what we saw in] the IMpower133 study.
What have we learned from the Phase 3 CASPIAN trial? How do you select the patients to receive this regimen compared to the IMpower133 regimen in practice?
The CASPIAN study also gives us another [option] for our patients. Instead of using aezolizumab, we are using durvalumab. The study looked at durvalumab [plus platinum/etoposide and] with tremelimumab [vs platinum/etoposide alone]. However, the problem became that the [the addition of tremelimumab] does not have [provide more benefit] than durvalumab [with platinum/etoposide]. We use a platinum-based backbone, along with etoposide and durvalumab. The difference is that in the maintenance study durvalumab was given once a month [while] Azeolizumab was given once every 3 weeks. At the same time, we use it in our practice anyway. I believe [the decision] really depends on [factors like] tolerability. Both schemes are very reasonable.
In February 2021, the FDA approved trilaciclib (Cosela) to reduce chemotherapy-induced bone marrow suppression in adult patients with ES-SCLC who were receiving certain chemotherapy agents. What was the impact of this decision on the paradigm?
Supporting growth factors has always been important to SCLC, especially [because of] the cytotoxic therapies we give [to our patients]. We used a granulocyte colony stimulating factor, and now we have another option [in the form of] this new CDK4 / 6 inhibitor.
It was nice to see that [that the agent] did not affect survival [of the patients who received it] in a negative way. We are very happy about it and [we will] use that [option] in our clinical practice. The more choices we have, the better it is for patients.
Switching to the second-line setting, in June 2020, lurbinectedin was also approved by the FDA for use in patients with metastatic SCLC following progression on platinum-based chemotherapy. How does the agent compare to standard topotecan?
We know that with first-line SCLC, many of our patients relapse and / or relapse. [Therefore], it is important to have [options in the] second line setting. We have always said that clinical trials are extremely important and that lurbinectedin has potential [option] beyond topotecan. As we know, topotecan has been approved as a second-line treatment; however, lurbinectedin appears to be better tolerated and shows [good] efficiency. [Moreover], topotecan is given on days 1-5, while [lurbinectedin] is really much easier to give. Having another choice makes a huge difference in practice.
How would you approach the choice between the 2 options?
Lurbinectedin is likely to become the standard of choice; it has been in our practice. This is for convenience – instead of days 1-5 it is [administered every] 21 days – as well as tolerance. I think he has a huge role for us, and we will continue to use him. He [will be] important for us to explore this [agent] in the first line [and learn] how we can overcome resistance in the second row.
The indication for pembrolizumab (Keytruda) in patients with metastatic SCLC who experienced disease progression during or after platinum-based chemotherapy and at least one prior line of treatment was recently withdrawn by the FDA. How do you foresee this impact on the use of the agent in this disease?
We were thrilled with the approval of pembrolizumab, but it has since been withdrawn by the FDA, and very reasonably – the end points [of the confirmatory trial] were not satisfied. If it doesn’t help our patients, it’s not worth it. [It begs the question], is pembrolizumab important? This could be very important in terms of early stage disease, first line, [and] in combination in other contexts. We dont do [currently] know and clearly we need to do more clinical trials.
Where should future efforts be concentrated?
Bispecific antibodies will be important, as well as bispecific T cell gear. Potentially, even CAR-T cell therapies will be important. All those [options] will lead to significant advances in the SCLC. Can immunotherapies be used with small molecule inhibitors? Can we [leverage] genomics or alterations in SCLC [to improve outcomes]? This remains to be determined, and this is where we need to [focus our] attention in [terms of] clinical tests.
Lung cancer remains a very difficult disease to treat. We have therapies that have revolutionized the way we think, but they’re not good enough; we have to do better. We must continue to [conduct] clinical tests [and encourage enrollment] so that we can make a difference. It is important to do research and fund it [for], SCLC as we did for non-small cell lung cancer, [where] a large number of codes are not respected. We still need to crack the code for SCLC even better.
- Goldman JW, Dvorkin M, Chen Y et al. Durvalumab, with or without tremelimumab, plus platinum – etoposide versus platinum – etoposide alone in the first-line treatment of large-stage small cell lung cancer (CASPIAN): updated results from a randomized, controlled phase 3 trial and open. Lancet Oncol. 2021; 22 (1): 51-65. doi: 10.1016 / S1470-2045 (20) 30539-8
- LB-100, carboplatin, etoposide and atezolizumab for the treatment of untreated extended stage small cell lung cancer. ClinicalTrials.gov. Updated March 15, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04560972
This article originally appeared on OncLive as “The future of SCLC treatment lies in innovative combinations of immunotherapy. “