Chemoimmunotherapy Regimens Improve Long-term Outcomes in Small Cell Lung Cancer

The addition of immunotherapy to carboplatin and etoposide improves survival for patients with small cell lung cancer (SCLC), making this a vital treatment option for this difficult to treat patient population. However, more research needs to be done to expand and personalize treatment alternatives in the platinum-sensitive and -refractory settings, according to Stephen V. Liu, MD.

In his presentation on SCLC delivered at the 40th Annual Chemotherapy Foundation Symposium^®, Liu highlighted findings from the phase 3 IMpower133 (NCT02763579) and CASPIAN (NCT03043872) trials evaluating the efficacy of adding immunotherapies to standard platinum-etoposide regimens in the first line. Both studies found improved overall survival (OS) with the addition of immunotherapy vs chemotherapy alone in patients with extensive-stage SCLC (ES-SCLC), leading to the FDA approval of PD-L1 inhibitors atezolizumab (Tecentriq) and durvalumab (Imfinzi), respectively.^1,2

“SCLC is a very aggressive disease, and we’ve unfortunately seen very few advances [in its treatment] over the past decades,” Liu said in an interview with OncLive^® following his presentation. “We know that chemotherapy can be very effective, but that benefit is transient. The integration of immunotherapy [with chemotherapy] finally [provides us with] more long-term, durable responses.”

In the interview, Liu discussed the effect of the FDA approval of atezolizumab on the development of other chemoimmunotherapy combination regimens, strategies to improve outcomes for this patient population, and ongoing efforts to expand and individualize treatment options for SCLC.

Liu is an associate professor of medicine at Georgetown University, and director of thoracic oncology and head of developmental therapeutics at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

OncLive^®: Could you speak to the significance of the phase 3 IMpower133 and CASPIAN trials in SCLC?

Liu: Two randomized phase 3 trials in the first-line setting show that adding immunotherapy to first-line platinum-etoposide chemotherapy improved survival. The first study, IMpower133, showed that adding the PD-L1 inhibitor atezolizumab to carboplatin plus etoposide extended OS, leading to [atezolizumab’s] approval in 2019. This was the first drug that showed any survival improvement in almost 4 decades.

The phase 3 CASPIAN study also showed [that] adding durvalumab [to platinum-etoposide produced] a modest but significant improvement in OS. Both of those drugs [showed] improvement in OS over chemotherapy and are now our standard of care.

The FDA approval of atezolizumab has led to investigations of atezolizumab-based combination regimens in patients with SCLC. What other combination therapies are being evaluated?

Atezolizumab is approved in the first-line setting based on the IMpower133 trial, [in which] its addition to carboplatin [plus] etoposide improved both progression-free survival and OS.

[To] build further on that regimen, we explored the addition of the anti-TIGIT antibody tiragolumab. It was explored because PVR, the ligand for TIGIT, is highly expressed in SCLC. [However,] adding tiragolumab did not improve survival compared with [atezolizumab plus carboplatin/etoposide.] [Although the study] did reinforce that [atezolizumab plus carboplatin/etoposide] is an excellent standard that extends to people with untreated brain metastases, targeting TIGIT was not successful in SCLC.

Another strategy to build on that regimen is the earlier integration of subsequent therapy. The approved second-line agent lurbinectedin [Zepzelca], a very active drug in SCLC, is being explored as a maintenance strategy [after first-line atezolizumab plus carboplatin/etoposide therapy] in the phase 3 IMforte trial [NCT05091567]. Patients will complete carboplatin/etoposide with atezolizumab, and then will be randomized to maintenance atezolizumab alone, or atezolizumab with lurbinectedin. IMforte is [currently] enrolling.

How can clinicians increase the chances that patients with SCLC who progress on first-line therapy can still receive second-line treatment?

Unfortunately, there is a lot of attrition in SCLC. Published data for patients who receive frontline therapy [shows that] only about half would get second-line therapy. This is why pursuing a maintenance strategy, or the earlier introduction of active agents is appealing. It’s hard to make promises, but close observation of patients on maintenance immunotherapy is [the best way to] ensure someone gets second-line therapy. This is not a case where you’re going to see someone once a year––scans [need to be done] every three months [to monitor] the brain if patients have not had prophylactic cranial radiation. [Overall, the best approach is] close monitoring [plus] educating patients to [identify and] immediately report concerning symptoms to their doctors.

Outside of the advances that have been made with immunotherapy, what other areas of interest in SCLC management are you excited about?

[When] I look at what’s on the horizon for SCLC, there are clearly active agents like lurbinectedin [being utilized.] Lurbinectedin has an accelerated approval in this space, and [shows] activity in both the refractory and [platinum-]sensitive setting. Its response rate in the chemo-refractory setting is 22%, [which is] better than other [approved] agents. In my own practice, I use lurbinectedin in the platinum-sensitive and refractory settings [rather than] rechallenge [patients] with platinum-etoposide.

[Still], we need other agents. [One promising agent,] liposomal irinotecan [nal-IRI; Onivyde] was unfortunately negative in a phase 3 trial vs topotecan. [Other trials aim to] bring together immune responses in SCLC [using] bispecific antibodies, like tarlatamab. [Tarlatamab] targets DLL3 [on tumor cells] and is highly expressed on the surface of CD3 [on T cells]. [It showed] modest response rates but durable responses and survival of over a year in the refractory setting, [which] is very encouraging.

What is your take-home message from this presentation?

[Ultimately,] the future [of SCLC] is going to look more appealing once we’re able to take advantage of different transcriptional subsets. All our strategies right now are empiric treatments, which is only going to lead to incremental gains. Being able to separate SCLC into different transcriptional subsets of lung cancer [will] allow us to further individualized therapy, [leading to improved] outcomes.

​​References

1. FDA approves Genentech’s Tecentriq in combination with chemotherapy for the initial treatment of adults with extensive-stage small cell lung cancer. News release. Genentech (Roche). March 18, 2019. Accessed November 23, 2022. https://bit.ly/2Y5jVkw
2. Imfinzi approved in the US for extensive-stage small cell lung cancer. News release. AstraZeneca. March 30, 2020. Accessed November 23, 2022. https://bit.ly/2UJKwTj