It is a storyline that sure lung most cancers specialists are little question uninterested in listening to: The usual of take care of small-cell lung most cancers (SCLC) has remained unchanged. Why? For one, “SCLC is characterised by a speedy doubling time and early metastases, and most sufferers current with extensive-stage or metastatic illness at analysis,” defined Paul A. Bunn, MD, of the College of Colorado in Aurora, and colleagues. One other is that, in contrast to with non-SCLC (NSCLC), accredited focused therapies that may take out plenty of recognized SCLC actionable mutations stay elusive.
So clinicians should soldier on with first-line remedy of etoposide and cisplatin or carboplatin, with or with out atezolizumab (Tecentriq) or durvalumab (Imfinzi), and second-line topotecan (Hycamtin) and lurbinectedin (Zepzelca). Within the RESILIENT Half 2 trial, Bunn’s group in contrast second-line liposomal irinotecan with topotecan in sufferers with SCLC who had progressed on or after first-line platinum-based chemotherapy.
In fact, there could be no RESILIENT Half 2 and not using a Half 1, which was reported in 2022 in Most cancers. Again in 2020, co-investigator David R. Spigel, MD, of the Sarah Cannon Analysis Institute in Nashville, advised VJOncology that, on the subject of RESILIENT, “it’s kind of of an outdated story that is new once more.”
“What I imply by that,” he stated, “is that we have at all times recognized that medicine which are topoisomerase inhibitors [Top1], like topotecan and irinotecan, are efficient in SCLC. It is simply that irinotecan has by no means actually established itself as a first-line and even second-line remedy, as a result of these different medicine exist. There has not likely been a bonus for irinotecan, so this drug [in RESILIENT] is a liposomal formulation of an outdated drug that we have at all times used — irinotecan [Camptosar].”
What did Bunn and colleagues reveal about RESILIENT Half 2 of their research within the Journal of Scientific Oncology? At about 18.4 months of follow-up, the median general survival (OS) was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan. The median progression-free survival (PFS) per blinded impartial central evaluation (BICR) was 4.0 versus 3.3 months, respectively, whereas the target response price (ORR) per BICR was 44.1% versus 21.6%, respectively.
The ORR is vital, though the OS major endpoint was not met: “There was a doubling of ORR … with no overlapping confidence intervals in sufferers receiving liposomal irinotecan in contrast with these receiving topotecan,” the crew wrote, including that the “security profile of liposomal irinotecan was in keeping with its recognized security profile; no new security considerations emerged.”
However the researchers additionally stated the trial outcomes “underline a persistent want for well-tolerated and efficacious remedy choices within the second-line setting. As well as, with growing uptake of first-line chemoimmunotherapy regimens, there’s an rising requirement to determine the efficacy of second-line therapies in sufferers who’ve acquired these regimens.”
If RESILIENT Half 2 was one step ahead for SCLC second-line remedy, a separate trial of elimusertib plus topotecan offered at ASCO’s 2024 annual assembly was one step again. Shannon Stockton, MD, of Vanderbilt-Ingram Most cancers Heart, additionally in Nashville, shared knowledge from an early-stage escalation research of elimusertib plus topotecan in SCLC and different strong tumors that did not fairly dwell as much as expectations. Little question Parth Anil Desai, MBBS, MD, of Fox Chase Most cancers Heart in Philadelphia, and colleagues hope for higher outcomes with their deliberate research of tazemetostat (Tazverik), a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, together with topotecan and pembrolizumab (Keytruda) in sufferers with recurrent SCLC.
Beneath are highlights from the posters by Stockton and Desai.
What was the impetus for the Experimental Therapeutics Scientific Trials Community research?
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 numerous cancers. Topotecan induces DNA injury. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and gastrointestinal most cancers xenografts when mixed with Top1 inhibitors. It is a section Ia research of elimusertib mixed with topotecan in grownup sufferers with refractory superior strong tumors for whom topotecan could be thought-about as a part of normal care. Sufferers with earlier topotecan publicity had been excluded. Main aims had been to evaluate security and tolerability and estimate the utmost tolerated dose (MTD) and really useful section II dose (RP2D) of the mixture.
What are some research particulars?
Stockton et al: The research mixture was assessed beginning at topotecan 1 mg/m2 IV (Day 1-Day 5) plus elimusertib 20 mg BID (Day 2, Day 5; cycle of 21 days). Eight sufferers had been handled in dose escalation. The preliminary two sufferers enrolled into dose stage (DL) 1 had dose-limiting toxicities [DLTs], with one affected person experiencing respiratory failure and cardiac arrest within the setting of pancytopenia associated to the research drug. Six sufferers had been subsequently enrolled in and acquired DL-1 (elimusertib decreased from 20 mg BID to twenty mg every day), and no DLTs had been noticed.
The disease-control price was 43% amongst evaluable sufferers together with one unconfirmed partial response. Median PFS survival within the RP2D cohort was 3.45 months. Notable grade 3+ treatment-related adversarial occasions had been neutropenia in 50%, thrombocytopenia in 37.5%, and cardiac arrest in 12.5%.
What’s the important take-home message?
Stockton et al: RP2D and MTD had been established for elimusertib together with topotecan. Dose escalation was notably restricted by myelotoxicity. Resulting from sponsor choice, the research was halted previous to deliberate expansions cohorts, however the idea of [elimusertib plus topotecan] stays related.
What was the impetus on your research?
Desai et al: Regardless of a extremely mutated genome, sufferers with SCLC derive little profit from immunotherapy. EZH2 is a grasp epigenetic regulator of SCLC neuroendocrine cell destiny and plasticity. That is an investigator-initiated, NCI Most cancers Remedy Analysis Program-sponsored, section I dose-escalation and dose-expansion research, which can consider the protection and tolerability of tazemetostat with topotecan and pembrolizumab.
Who’s eligible?
Desai et al: Grownup sufferers with relapsed/recurrent SCLC after at the very least platinum doublet (restricted stage-SCLC) or chemoimmunotherapy (in depth stage-SCLC) and ECOG efficiency 0-1 are eligible.
What are another research particulars?
Desai et al: The routine design includes a 7-day “run-in” of oral tazemetostat BID adopted by 21-day cycles of tazemetostat (1-21 days), IV topotecan (day 1-5), and IV pembrolizumab (day 1).
The research includes assortment of obligatory biopsies at pre-treatment and post-treatment (cycle 1) to achieve insights into the mechanism of motion and resistance of the mixture utilizing single-cell and spatial transcriptomic approaches.
Learn the research by Paul Bunn and colleagues right here.
RESILIENT Half 2 is supported by Ipsen Biopharmaceuticals.
Bunn, Spigel, and co-authors disclosed a number of relationships with business, together with Ipsen.
