SCLC's Treatment Arsenal Improving

For decades, etoposide/platinum (EP) chemotherapy has been standard for small cell lung cancer (SCLC), and fresh options are sorely needed for an intractable, fast-spreading tumor type in which the initial diagnosis is often extensive-stage (ES) disease. There are glimmers of hope: Adding immune checkpoint inhibition (ICI) to the EP backbone, for instance, appears to provide durable benefit. Meanwhile, based on early trial results, other combinations and an investigational bispecific T-cell engager are showing second- or later-line potential.

Long-term follow-up data from the phase III KEYNOTE-604 study were recently presented at the International Association for the Study of Lung Cancer's 2022 World Conference on Lung Cancer (WCLC) in Vienna, Austria. Charles Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, reported that among 453 patients with newly diagnosed ES-SCLC randomly assigned to receive pembrolizumab (Keytruda; Merck) or placebo alongside EP chemotherapy, overall survival (OS) at 3 years was 15.5 months versus 5.9 months. The 3-year progression-free survival (PFS) was 6.9 months versus 0.5 months.

Short-lived treatment responses and rapid disease progression are typical of ES-SCLC, so “to me, the PFS difference is even more impressive,” Rudin remarked.

Rudin also highlighted 18 patients who stayed the course with KEYNOTE-604’s full treatment plan: four cycles of pembrolizumab–EP and then 31 cycles of maintenance pembrolizumab. They had durable responses—two complete—and 14 are alive today, 4 years after the trial started.

“We couldn't find any clinical parameters that would allow us to distinguish these patients as being particularly likely to do well,” Rudin added, “but additional molecular analyses are underway, so stay tuned.”

Discussant Virginie Westeel, MD, PhD, of the University of Franche-Comté in Besançon, France, observed that similar results have been seen in four other phase III studies exploring ICI plus EP for newly diagnosed ES-SCLC: IMpower-133, CASPIAN, CAPSTONE-1, and ASTRUM-005, respectively assessing atezolizumab (Tecentriq; Genentech), durvalumab (Imfinzi; AstraZeneca), adebrelimab (Atridia), and serplulimab (Shanghai Henlius Biotech).

To Westeel, KEYNOTE-604 supports ICI plus EP as a reasonable first-line strategy for ES-SCLC. SCLC is highly heterogeneous, she added, with a fourth subtype, I, recently unearthed and characterized (Cancer Cell 2021;39:346–60). Each of the other three subtypes—A, N, and P—likely responds to different classes of drugs, and I appears more sensitive than the rest to immunotherapy, so “new combinations based on disease molecular profiles will be important.”

For relapsed/refractory ES-SCLC, the treatment landscape is even bleaker—topotecan is the only FDA-approved option, with a historical objective response rate (ORR) of 15%. Researchers are pursuing new possibilities, and early data from two phase II trials were featured at the WCLC: Both evaluated temozolomide (TMZ) in combination with either the PD-1 inhibitor nivolumab (Opdivo; Bristol Myers Squibb) or the PARP inhibitor talazoparib (Talzenna; Pfizer).

Dwight Owen, MD, of The Ohio State University in Columbus, reported that among 25 patients given nivolumab–TMZ, the ORR was 28%. However, “responses were generally not durable,” he said, “and only occurred in patients sensitive to [first-line] platinum chemotherapy.” The median PFS was 2.4 months, and the median OS was 6.4 months.

Westeel was intrigued by the investigators’ analytical observation that responding patients started out with low baseline levels of natural killer cells, which increased over time. It merits further probing in her view.

Jonathan Goldman, MD, of the University of California, Los Angeles, reported that among 28 patients, the ORR with talazoparib–TMZ was 39.3%, the median PFS 4.3 months, and the median OS 11.9 months. “Ours is the second study to demonstrate benefit with PARP inhibition plus temozolomide” in SCLC, he said (Cancer Discov 2019;10:1372–87).

Goldman also highlighted findings from an exploratory circulating tumor DNA analysis, in which treatment-emergent ATM mutations correlated with disease control and a trend toward improved PFS. “It supports our proposed mechanism of action—that talazoparib-induced genomic instability could significantly potentiate temozolomide's activity,” he said.

“Information on Schlafen 11 [SLFN11] expression would have been useful too; it's the best-known biomarker of PARP inhibition sensitivity,” Westeel remarked. That aside, she was encouraged by the median OS and found it “striking that roughly half the patients who were resistant to platinum chemotherapy responded” to talazoparib–TMZ.

Also at the WCLC, Hossein Borghaei, DO, of Fox Chase Cancer Center in Philadelphia, PA, provided an update on a phase I trial of tarlatamab (Amgen), a bispecific T-cell engager that targets DLL3, which is overexpressed in SCLC. Among 105 patients, one third of whom had received at least three drug regimens, the ORR was 23%, including two complete responses. Roughly 37% of patients experienced significant tumor shrinkage, and the median PFS and OS were 3.7 months and 13.2 months, respectively.

Tarlatamab's main side effects were low-grade cytokine release syndrome and dysgeusia, Borghaei added. A phase II registrational trial, DeLLphi-301, is enrolling patients with disease progression after at least two other treatments.

The 2019 failure of AbbVie's DLL3-targeting antibody–drug conjugate, Rova-T, notwithstanding, Westeel was cautiously heartened by tarlatamab's preliminary data. DLL3 remains of considerable therapeutic interest, she said; another T-cell engager in the works is HPN328 (Harpoon Therapeutics), and results thus far seem in line with tarlatamab's.

Overall, “there are many exciting targets, drugs, and combinations that warrant further testing,” Westeel concluded, “but we really still lack validated biomarkers” to guide patient selection. She also reminded attendees of SKYSCRAPER-02’s results: Earlier this year, the investigational TIGIT inhibitor tiragolumab (Genentech) was found not to benefit patients with ES-SCLC when added to atezolizumab and EP chemotherapy.

“This negative phase III trial came directly from a dose-expansion phase I study,” Westeel pointed out. Speed may seem critical for such a tough-to-treat cancer, but “we have to avoid being hasty—bypassing phase II—and accept that, as Confucius said, the man who moves mountains begins by carrying away small stones.” –Alissa Poh