Navigating Newfound Options in SCLC With Immunotherapy and Lurbinectedin

While the treatment paradigm of small cell lung cancer (SCLC) has experienced rapid expansion since the introduction of immunotherapy, said Rafael Santana-Davila, MD, much more lies ahead with combinations and patient selection for this class of agents and others. 

“Treatment of SCLC is always changing,” said Santana-Davila. “The addition of atezolizumab [Tecentriq] and durvalumab [Imfinzi] to chemotherapy are [now] standards of care that we should use.”

Additionally, in June 2020, the FDA granted an accelerated approval to lurbinectedin (Zepzelca) for the treatment of patients with metastatic SCLC with disease progression, following platinum-based chemotherapy.¹ The regulatory decision was based on findings from a phase 2 basket trial (NCT2454972), in which lurbinectedin induced an overall response rate of 35.2% among 105 patients.² 

In an interview with OncLive^® during a 2020 Institutional Perspectives on Cancer webinar, Santana-Davila, medical director of the Infusion and Pharmacy Services and an attending physician at the Seattle Cancer Care Alliance, an associate professor of medicine and oncology at the University of Washington (UW) School of Medicine, a physician at UW Medicine, and an associate professor within the Clinical Research Division at the Fred Hutchinson Cancer Research Center, discussed the introduction of immunotherapy and lurbinectedin to the SCLC armamentarium, as well as areas in need of additional research.

OncLive^®: Multiple studies have demonstrated the efficacy of immunotherapy in SCLC. Could highlight the significance of the IMpower133 trial?

Santana-Davila: At least 4 clinical trials have addressed the use of immunotherapy in the treatment of [patients with] SCLC. [IMpower133 was] the first trial and [evaluated] atezolizumab. All [4] studies randomized patients to immunotherapy and chemotherapy [or] chemotherapy alone––the standard of care.

[IMpower133] was a placebo-controlled, phase 3 study in which patients were randomized to atezolizumab versus carboplatin and etoposide. The results showed an overall survival [OS] advantage [with atezolizumab]. 

How did data from the CASPIAN trial add to the development of immunotherapy in SCLC? What distinguished CASPIAN from IMpower133?

The CASPIAN study was slightly different in the sense that it was not placebo-controlled, but rather open-label. Patients knew what they were getting, and physicians knew what [they] were [giving]; that was the main difference. Another [difference] was that in [both] arms, investigators were allowed to use cisplatin, which is commonly used in Europe. In the standard-of-care arm, patients could [receive therapy] for 6 cycles. In [IMpower133] and in the investigator’s choice arm of the CASPIAN study, patients could get up to 4 cycles of chemotherapy. 

Aside from that, the CASPIAN study was a 3-arm trial with standard-of-care chemotherapy alone, carboplatin or cisplatin with etoposide plus durvalumab, and carboplatin or cisplatin, etoposide, durvalumab, and tremelimumab, which is a CTLA-4 antagonist. That was the design of the study. 

The results confirmed data from [IMpower133], demonstrating that adding immunotherapy can improve OS [in patients with SCLC]. The OS went from about 10 months to 12 months with a very similar hazard ratio as with atezolizumab. 

From what we know, atezolizumab and durvalumab are similar agents and are arguably interchangeable.

With regard to the CASPIAN study, the other arm of durvalumab and ipilimumab [Yervoy] was negative. Although the P value was less than .05, [the investigators] had agreed that the P value had to be less than .41 to be positive. That also confirmed what we knew before in SCLC: CTLA-4 and PD-L1 inhibition are not effective [in combination] and should therefore not be [given] outside of a clinical trial. 

What other studies have shed light on the utility of immunotherapy in SCLC?

I mentioned there were 4 studies. One of the other studies was a phase 2 study for nivolumab [Opdivo] that also showed an OS advantage. The fourth study was with pembrolizumab [Keytruda], which was not positive because of how it was designed.

What questions remain with regard to PD-L1 as a biomarker in SCLC? 

The main question that we have right now is that, in contrast to non–small cell lung cancer where PD-L1 serves as a biomarker, we don’t have anything that differentiates who is more likely to benefit from treatment in SCLC. One of the areas of future research should be what patients should receive, and are there patients who need more aggressive therapy with added immunotherapy?

We know that CTLA-4 and PD-L1 inhibition do not appear to confer an advantage [in an all-comer patient population]. However, we know that patients do respond to [the combination], so if we can find biomarkers that will let us know who those patients are, that would be ideal. However, at this point, we don’t have that.

Many clinical trials are examining [biomarkers of response]. Every clinical trial right now is looking at a lot of biomarkers, but so far, I don’t know of any that are likely to be used in the near future

Lurbinectedin is an active agent in SCLC. What is unique about this agent?

[Lurbinectedin] is a new form of chemotherapy. I don’t think we know yet what its exact mechanism of action is. It was initially developed as a single agent that showed some responses in SCLC. The investigators did not think that lurbinectedin by itself would be enough, so that is why there are [positive] preclinical data of lurbinectedin in combination with doxorubicin. 

At the same time, data from a phase 2 basket trial showed efficacy with [lurbinectedin as monotherapy]. In that trial, around 107 patients were treated [with lurbinectedin] after initial platinum-based doublet therapy. [Data showed] an increase in response rate, somewhere around 35%. However, this was a phase 2 study, which can sometimes be premature. When we study [phase 2 trials] further, the effectiveness [of the investigational regimens] can go down. We don’t know what is going to [be found] in the phase 3 study.

We know that lurbinectedin is now approved, and we have started to use it. However, I don’t know how we are going to be able to interpret the results of the study because it is basically another combination. Again, we will see what those results are and decide based on them. [Regardless,] lurbinectedin is clearly active in SCLC and is a welcomed addition to our armamentarium.

Could you expand on the goals of the phase 3 ATLANTIS study?

[The preclinical data] from the phase 1 study showed that [lurbinectedin] was an active [agent in] combination against SCLC. That then led to the ATLANTIS study. 

The ATLANTIS study is a phase 3 trial that randomized patients to the combination of lurbinectedin and doxorubicin versus the current second-line standard, which is topotecan or cyclophosphamide, doxorubicin, and vincristine [CAV]. CAV is commonly used in Europe as a second-line treatment. The end point was OS. I believe the trial has completed accrual, and now we are waiting for events to occur so the results can read out. 

How do you expect to integrate the results of the ATLANTIS trial into the current paradigm if they are positive?

Because this study used a different dose of lurbinectedin and used the agent in combination with doxorubicin, we don’t know how [we will] interpret the results. If [ATLANTIS] is positive and lurbinectedin and doxorubicin [is superior] to topotecan and CAV, the question will be, How does it compare with lurbinectedin alone? Is it better? Is it worse? We won’t know that, so it will require another study. Yes, we will probably use [safety] data to decide whether the combination should be explored versus single-agent lurbinectedin. 

However, if it is a negative study and the combination is equal or worse than topotecan or CAV, does that indicate that lurbinectedin by itself will have similar efficacy [to the combination] and is it also worse than topotecan? We don’t know. Again, it is going to be difficult to interpret, so we will have to see what it shows before we can say anything.

Are any next steps planned to evaluate lurbinectedin in other combinations?

There are at least a few planned studies using the agent in combination with immunotherapy to see if that may augment the immune response. I believe that lurbinectedin is also being studied in the first-line setting in combination with carboplatin to see if that will be [superior to] etoposide. I also heard that [a study may give lurbinectedin] as maintenance therapy after carboplatin/etoposide. In SCLC at least, the drug is very new, so there are many ways that it should be studied to find its niche in this space.

With regard to ongoing research efforts, what data are coming to light with transcription factor alterations? 

SCLC has a bunch of abnormalities that have to do with transcription factor alterations. Several lines of research are showing that [SCLC] may not be 1 disease, but rather several that depend on abnormal transcription factors that behave differently. [Research efforts] are trying to categorize SCLC by [transcription factor abnormalities]. Several clinical trials are going to use that. 

There is also research [evaluating] what to do with radiation therapy. Many times, we used radiation after [the] CASPIAN [trial regimen], in particular for patients who have mostly thoracic disease. We don’t know what to do with a PD-L1 inhibitor at that time. [Many] clinical studies are addressing that question. 

References

1. PharmaMar announces the US FDA approval of lurbinectedin (Zepzelca) for the treatment of metastatic small cell lung cancer. News release. June 15, 2020. Accessed October 16, 2020. bit.ly/3hzSAAK
2. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1