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It's a storyline that certain lung cancer specialists are no doubt tired of hearing: The standard of care for small-cell lung cancer (SCLC) has remained unchanged. Why? For one, "SCLC is characterized by a rapid doubling time and early metastases, and most patients present with extensive-stage or metastatic disease at diagnosis," explained Paul A. Bunn, MD, of the University of Colorado in Aurora, and colleagues. Another is that, unlike with non-SCLC (NSCLC), approved targeted therapies that can remain elusive.

So clinicians must soldier on with first-line therapy of etoposide and cisplatin or carboplatin, with or without atezolizumab (Tecentriq) or durvalumab (Imfinzi), and second-line topotecan (Hycamtin) and lurbinectedin (Zepzelca). In the RESILIENT Part 2 trial, Bunn's group compared second-line liposomal irinotecan with topotecan in patients with SCLC who had progressed on or after first-line platinum-based chemotherapy.

Of course, there would be no RESILIENT Part 2 without a Part 1, which was reported in 2022 in . Back in 2020, co-investigator David R. Spigel, MD, of the Sarah Cannon Research Institute in Nashville, told that, when it comes to RESILIENT, "it's a bit of an old story that's new again."

"What I mean by that," he said, "is that we've always known that drugs that are topoisomerase inhibitors [Top1], like topotecan and irinotecan, are effective in SCLC. It's just that irinotecan has never really established itself as a first-line or even second-line therapy, because those other drugs exist. There has not really been an advantage for irinotecan, so this drug [in RESILIENT] is a liposomal formulation of an old drug that we've always used -- irinotecan [Camptosar]."

What did Bunn and colleagues reveal about RESILIENT Part 2 in their study in the ? At about 18.4 months of follow-up, the median overall survival (OS) was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan. The median progression-free survival (PFS) per blinded independent central review (BICR) was 4.0 versus 3.3 months, respectively, while the objective response rate (ORR) per BICR was 44.1% versus 21.6%, respectively.

The ORR is key, even though the OS primary endpoint was not met: "There was a doubling of ORR ... with no overlapping confidence intervals in patients receiving liposomal irinotecan compared with those receiving topotecan," the team wrote, adding that the "safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged."

But the researchers also said the trial results "underline a persistent need for well-tolerated and efficacious treatment options in the second-line setting. In addition, with increasing uptake of first-line chemoimmunotherapy regimens, there is an emerging requirement to establish the efficacy of second-line therapies in patients who have received these regimens."

If RESILIENT Part 2 was one step forward for SCLC second-line treatment, a separate trial of elimusertib plus topotecan presented at ASCO's 2024 annual meeting was one step back. Shannon Stockton, MD, of Vanderbilt-Ingram Cancer Center, also in Nashville, shared data from an early-stage escalation study of elimusertib plus topotecan in SCLC and other solid tumors that didn't quite live up to expectations. No doubt Parth Anil Desai, MBBS, MD, of Fox Chase Cancer Center in Philadelphia, and colleagues hope for better results with their (Tazverik), a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, in combination with topotecan and pembrolizumab (Keytruda) in patients with recurrent SCLC.

Below are highlights from the posters by Stockton and Desai.

What was the impetus for the Experimental Therapeutics Clinical Trials Network study?

Stockton et al: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single-strand DNA abnormalities in various cancers. Topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and gastrointestinal cancer xenografts when combined with Top1 inhibitors. This is a phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the combination.

What are some study details?

Stockton et al: The study combination was assessed starting at topotecan 1 mg/m² IV (Day 1-Day 5) plus elimusertib 20 mg BID (Day 2, Day 5; cycle of 21 days). Eight patients were treated in dose escalation. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities [DLTs], with one patient experiencing respiratory failure and cardiac arrest in the setting of pancytopenia related to the study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg daily), and no DLTs were observed.

The disease-control rate was 43% among evaluable patients including one unconfirmed partial response. Median PFS survival in the RP2D cohort was 3.45 months. Notable grade 3+ treatment-related adverse events were neutropenia in 50%, thrombocytopenia in 37.5%, and cardiac arrest in 12.5%.

What is the main take-home message?

Stockton et al: RP2D and MTD were established for elimusertib in combination with topotecan. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts, but the concept of [elimusertib plus topotecan] remains relevant.

What was the impetus for your study?

Desai et al: Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 is a master epigenetic regulator of SCLC neuroendocrine cell fate and plasticity. This is an investigator-initiated, NCI Cancer Therapy Evaluation Program-sponsored, phase I dose-escalation and dose-expansion study, which will evaluate the safety and tolerability of tazemetostat with topotecan and pembrolizumab.

Who is eligible?

Desai et al: Adult patients with relapsed/recurrent SCLC after at least platinum doublet (limited stage-SCLC) or chemoimmunotherapy (extensive stage-SCLC) and ECOG performance 0-1 are eligible.

What are some other study details?

Desai et al: The regimen design involves a 7-day "run-in" of oral tazemetostat BID followed by 21-day cycles of tazemetostat (1-21 days), IV topotecan (day 1-5), and IV pembrolizumab (day 1).

The study involves collection of mandatory biopsies at pre-treatment and post-treatment (cycle 1) to gain insights into the mechanism of action and resistance of the combination using single-cell and spatial transcriptomic approaches.

Read the study by Paul Bunn and colleagues here and expert commentary about it here.