Next Steps in Small Cell Lung Cancer Feature Closer Eye on Immunotherapy, Lurbinectedin

In small cell lung cancer (SCLC), long-term follow-up with immunotherapy and randomized studies of lurbinectedin (Zepzelca) will unveil the next chapter of treatment decision making, explained Benjamin Drapkin, MD, PhD, adding that nonresponders to checkpoint inhibitors remain a key challenge.​

“We have a lot of challenges in the first-line [setting] yet to overcome, including the 80% to 90% of patients who don't derive benefit and identifying the patients who do,” said Drakin. “In the second-line setting, there are a lot of new agents that are being tested, such as lurbinectedin, that show promising activity. [Physicians should] stay tuned for the randomized controlled trials that will,hopefully, show some superiority.”

Atezolizumab (Tecentriq) and durvalumab (Imfinzi) each have FDA indications in the frontline setting in combination with chemotherapy.

In the phase 3 IMpower133 trial, patients with treatment-naïve extensive-stage (ES) SCLC received carboplatin/etoposide plus either atezolizumab or placebo. Updated data that were presented at the 2020 AACR Virtual Annual Meeting II showcased that the addition of atezolizumab yielded an overall survival (OS) benefit when compared with carboplatin plus etoposide alone, but further follow-up is anticipated.¹

The results of the phase 3 CASPIAN trial additionally compared durvalumab plus platinum-etoposide, durvalumab plus tremelimumab and platinum-etoposide, and platinum-etoposide alone in untreated patients with ES-SCLC. The trial further solidified the role of immune checkpoint inhibitors in the first-line setting by demonstrating a notable benefit in OS with the PD-L1 inhibitor.²

The challenge, Drapkin mentioned, lies in identifying the patient subgroups who will likely respond to such combinations.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Drapkin, an assistant professor of Internal Medicine at University of Texas Southwestern Medical Center, discussed the road ahead in SCLC research, and the challenges that still need to be solved in the first- and second-line settings .

OncLive®: Since the advent of immunotherapy in SCLC, what next steps need to be taken regarding treatment?

Drapkin: Certainly, SCLC is a recalcitrant disease. There was very little progress made in the first-line and relapsed setting from about 1990 until 2018. Not to be too reductive or dismiss all of the heroic efforts that we've made and that the people who came before me have made, but the standard first-line therapy with either cisplatin or carboplatin plus etoposide didn't really change until 2 years ago. That's a very long time for stasis in a field. Then, with the advent of immune checkpoint blockade, that was the first time that anything changed. We now have 2 PD-L1 inhibitors added to the armamentarium with atezolizumab and durvalumab added to first-line platinum-based therapy plus etoposide. There's a real benefit for a significant subset of patients—about 10% to 15%—and it seems possible that other immune checkpoint blockade agents would have similar benefit. This is a major change for a minority of patients who suffer from ES-SCLC.

The [next steps] that the field needs to [determine include] coming up with therapies that provide durable benefit for the majority of patients, or to come up with new ways to identify patients who are in that small subset of 10% to 15%. Those are really the next challenges to tackle in the first-line setting.

In the relapsed setting, there has been a lot of activity and a lot of compelling clinical trials and strategies leveraging PARP inhibitors or immune checkpoint blockade agents, which are showing some promise and increasing response rates in patients with relapsed SCLC.

There really wasn't anything that was added specifically for the second-line [setting] and received FDA approval, specifically for that indication, until lurbinectedin, which is a DNA-binding agent that seems to target transcription in SCLC. We'll see how effective that is in comparison with standard topotecan or cyclophosphamide plus doxorubicin and vincristine combination therapy in the upcoming years with the ATLANTIS trial, but it's exciting [nonetheless].

What do you find most interesting about the activity with durvalumab and atezolizumab regimens?

In the IMpower133 trial, [the addition of atezolizumab] didn't seem to significantly increase response rates. The percentage of patients who [experience] a significant reduction in tumor burden is about 60% to 65% with and without immune checkpoint blockade, respectively. But, the durability of those responses increased for a subset of patients on immune checkpoint blockade.

I'm not sure that the median increase in OS or progression-free survival (PFS) really captures the benefit because it does seem to have been restricted to between 10% and 20% of patients [according to the] interim analysis published in the New England Journal of Medicine. In the follow-up [data], there's a tail of significant benefit.

[Similar benefit was seen in] the CASPIAN trial with durvalumab, but in that trial—and we'll see how significant it ends up being—there was an advantage in overall response rate (ORR), as well. About 58% to 67% of patients in the control arm with platinum etoposide alone [saw benefit], but the same overall pattern for the first 4 to 6 months are being dominated by the sensitivity or resistance to platinum plus etoposide. Thereafter, the curve with the immune checkpoint blockade starts to diverge, as you start to see this durable benefit in a subset of patients who received a new checkpoint blockade.

We also saw the results from the third CASPIAN arm, with tremelimumab, this year. Were you surprised that there wasn't a significant additive benefit with the third drug?

I was a little bit surprised that it didn't seem to be more beneficial, but it's telling us something very important about the overall biology of the disease, which is that there's about 1 in 8 to 1 in 10 patients who are really going to benefit from this strategy, and they're going to benefit with or without the addition of anti­­–CTLA-4.

How do you decide which checkpoint inhibitor to pursue?

[Durvalumab and atezolizumab] are both checkpoint inhibitors and they're both FDA approved. The CASPIAN trial has the advantage of greater flexibility in choice of immune checkpoint blockade and choice of [chemotherapy] agent. Investigators had the choice to incorporate carboplatin or cisplatin and there was a wider range of doses that were permitted [in the trial]. Time will tell [which agent is best to use]. We will really have to wait and see for probably quite a long time for that tail of 10% to 20% of patients [in the IMpower133 trial], to see overall which seems to have a greater benefit.

How is lurbinectedin being utilized in clinical practice

I haven’t used lurbinectedin in practice yet. It’s exciting that there is a new drug added to the armamentarium for second-line therapy in SCLC. It received accelerated approval; there are limitations there with the basket trial where lurbinectedin received approval primarily [based on a] high ORR of about 35% as opposed to a demonstration of making patients live significantly longer or feel significantly better. However, it's a promising [agent] and it's good to have options. In general, it was a manageable therapy with a good safety profile. The most exciting results are probably to come with the ATLANTIS trial looking at lurbinectedin in combination with doxorubicin or other agents, but time will tell.

What is the rationale to explore of PARP inhibitors in SCLC?

There have been a number of second-line trials with PARP inhibitors in SCLC. A lot of the preclinical rationale comes from research from Lauren A. Byers, MD, of The University of Texas MD Anderson Cancer Center, [and her] group; Charles M. Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center; and Yves Pommier, MD, PhD, of the National Cancer Institute.

Collectively, what they found is that although SCLC doesn't seem to have the classic features of a tumor that's going to be sensitive to PARP inhibitors, such as the defects in BRCA1/2 or homologous recombination [repair genes], it expresses a lot of PARP1. The preclinical models are exquisitely sensitive. It may be because this tumor grows very fast and is generally dependent on DNA damage repair pathways because so many of the classic checkpoints are mutated or missing—owing to loss of [retinoblastoma protein], p53, and hallmarks of small cell genomics.

The response rates with combinations of either veliparib (ABT-888) or olaparib (Lynparza) plus single-agent DNA-damaging agents, such as temozolomide (Temodar), have been really promising. Again, [the benefit is] sort of similar to lurbinectedin [in that it elicits responses and is tolerable], but in those settings, we haven't seen the dramatic prolongation of PFS or OS. That’s really what we're waiting for [with] second-line agents.

References

1. Horn L, Liu SV, Mansfield AS, et al. IMpower133: Updated OS and exploratory analyses of first-line (1L) atezolizumab (atezo) + carboplatin (C) + etoposide (E) in extensive-stage SCLC (ES-SCLC). Presented at: American Association for Cancer Research Virtual Annual Meeting II; June 22-24, 2020; Virtual. Abstract CT220.

2. Paz-Ares LG, 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 9002). doi:10.1200/JCO.2020.38.15_suppl.9002

​