Future of SCLC Treatment Lies in Innovative Immunotherapy Combos

The phase 3 IMpower133 trial (NCT02763579), which examined atezolizumab (Tecentriq) plus platinum-based chemotherapy and etoposide in patients with untreated extensive-stage small cell lung cancer (ES-SCLC), helped lay the foundation for the exploration of other novel immunotherapy combinations, according to Ravi Salgia, MD, PhD.

In the phase 3 CASPIAN trial (NCT03043872), investigators examined the use of first-line durvalumab (Imfinzi) plus the same chemotherapy backbone in patients with ES-SCLC.¹ The combination yielded a durable improvement in overall survival, but the addition of tremelimumab did not appear to elicit any further statistically significant improvement.

Now a phase 1 study (NCT04560972) will further build off the IMpower133 regimen by examining the safety of the novel agent LB-100 in combination with carboplatin, etoposide, and atezolizumab in patients with untreated ES-SCLC.²

“It is important for us to realize that the tumor mutational burden for SCLC is very high,” Salgia said. “We need to be able to [consider whether] immunotherapy [may] work even better [when used] in combination with chemotherapy or other therapeutic strategies.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on lung cancer, Salgia, a medical oncologist and Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope, discussed pivotal trials that have shaken up the SCLC treatment paradigm and novel immunotherapy regimens under investigation.

OncLive^®: What is your approach for selecting treatment for 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 there are 2 varieties of [the disease] that we consider in terms of the staging: LS-SCLC and ES-SCLC. For [patients with] LS-SCLC, we still [administer] chemotherapy and radiation therapy [with consideration] for prophylactic cranial radiation. For those with [ES-SCLC], we are changing the paradigm. Currently, we are using chemotherapy with immunotherapy. After the first line of therapy fails, [we have a] second-line option, which is lurbinectedin [Zepzelca]. Of course, we really try to emphasize [enrollment to] clinical trials, as well.

Starting in the frontline setting, how are you applying the findings from the pivotal phase 3 IMpower133 trial to clinical practice?

Results have [demonstrated] that platinum-based chemotherapy with etoposide plus atezolizumab [yields] better survival. That is revolutionary for us, and we are using [atezolizumab] in our clinical practice. It is important to realize that the severity of the adverse effects was not worse than [what was reported in] the chemotherapy arm.

An ongoing study that is open at City of Hope is building on the success seen with the IMpower133 regimen. Could you highlight this research?

For ES-SCLC, we are using carboplatin and etoposide with atezolizumab, as an example. However, we know patients can recur and relapse, so we wanted to make that better. In our laboratory, we had discovered that the PP2A pathway in SCLC is very important. We can inhibit that pathway with a drug called LB-100. We are using a backbone of the IMpower133 regimen—carboplatin and etoposide with atezolizumab—and combining it with LB-100. We are going to be publishing [these data] relatively soon. It is important to realize it is a phase 1 study, but we are quite hopeful that this [research] will [result in] revolutionary breakthroughs.

Does LB-100 have a safety profile that makes it amenable for use in a 4-drug combination?

The initial LB-100 study [that examined the] drug by itself was done here, at City of Hope, and that [research] was published by Vincent Chung, MD, and colleagues. The safety 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 are very much hoping that the toxicity is no different from [what we saw in] the IMpower133 study.

What has been learned from the phase 3 CASPIAN trial? In practice, how do you select which patients should receive this treatment regimen vs the IMpower133 regimen?

The CASPIAN study also gives us another [option] for our patients. Instead of utilizing atezolizumab, we utilize durvalumab. The study looked at durvalumab [plus platinum/etoposide and] with tremelimumab [vs platinum/etoposide alone]. However, the issue became that the [the addition of tremelimumab] did not [provide more benefit] than durvalumab [with platinum/etoposide]. We are using a platinum-based backbone, with etoposide and durvalumab. The difference is that in the context of the maintenance study, durvalumab was given once a month [whereas] atezolizumab was given once every 3 weeks. At the same time, we use it in our practice either way. I do believe [the decision] is really dependent on [factors like] tolerability. Both of the regimens 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. How did this decision affect the paradigm?

Growth factor support has been always important for SCLC, especially [because of] the cytotoxic therapies that we give [to our patients]. We have used 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 [the agent] did not affect the survival [of the patients who received it] in a negative way. We are very happy with that, and [we will] be utilizing that [option] in our clinical practice. The more choices we have, the better it is for patients.

Shifting 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 a platinum-based chemotherapy. How does the agent compare with standard topotecan?

We know that in the first-line setting of SCLC, many of our patients relapse and/or recur. [Therefore], it is important to have [options in the] second-line setting. We have always said that clinical trials are incredibly important, and lurbinectedin provides a potential [option] beyond topotecan. As we know, topotecan has been approved as a second-line therapy; however, lurbinectedin seems to be better tolerated and is showing [good] efficacy. [Moreover], topotecan is given on days 1 through 5, whereas [lurbinectedin] is really much easier to give. Having another choice makes a huge difference in practice.

How would you approach choosing between the 2 options?

Lurbinectedin is probably going to become the standard of choice; it has been in our practice. It is because of convenience—instead of days 1 through 5, it is [administered every] 21 days—as well as tolerability. I do think it has a huge role for us, and we will continue to utilize it. It [will be] important for us to explore this [agent] in the first-line setting [and learn] how we can overcome resistance in the second-line setting.

The indication for pembrolizumab (Keytruda) in patients with metastatic SCLC who experienced disease progression on or after platinum-based chemotherapy and at least 1 prior line of treatment was recently withdrawn by the FDA. How do you foresee this affecting the use of the agent in this disease?

We had been excited about the approval of pembrolizumab, but it has since been withdrawn by the FDA, and very reasonably so—the end points [of the confirmatory trial] have not been met. If it does not help our patients, it is not worth it. [It begs the question]: Is pembrolizumab important? It could be very important in terms of early- stage disease, in the first-line setting, [and] in combination in other settings. We do not [currently] know, and, clearly, we need to do more clinical trials.

Where should future efforts be focused?

Bispecific antibodies as well as bispecific T-cell engagers are going to be important. Potentially, even chimeric antigen receptor T-cell therapies will be significant. All of those [options] will lead to significant advances in SCLC. Can one use immunotherapeutics with small molecule inhibitors? Can one [leverage] the genomics or alterations in SCLC [to improve outcomes]? That is to be determined, and that is where we need to [focus our] attention in [terms of] clinical trials.

Lung cancer is still a very tough disease to treat. We have some therapeutic options that have revolutionized our way of thinking, but it is not good enough; we need to do better [for our patients]. We need to continue to [conduct] clinical trials [and encourage enrollment] so we can make a difference. It is important to do research in, and fund research [for], SCLC, [just] as we have done for non–small cell lung cancer, [where] many of the codes are being broken. We need to break the code even better for SCLC.

References

1. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8
2. LB-100, carboplatin, etoposide, and atezolizumab for the treatment of untreated extensive-stage small cell lung cancer. ClinicalTrials.gov. Updated March 15, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04560972