Second-Line Liposomal Irinotecan Fails to Improve OS, PFS Over Topotecan in SCLC

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Single-agent liposomal irinotecan (Onivyde) resulted in a similar median overall survival (OS) and progression-free survival (PFS) to that achieved with topotecan in patients with small cell lung cancer (SCLC) that had progressed on or following frontline platinum-based chemotherapy, according to data from part 2 of the phase 3 RESILIENT trial (NCT03088813).¹

Data presented during the 2023 European Lung Cancer Congress showed that the median OS with liposomal irinotecan (n = 229) was 7.9 months (95% CI, 6.9-9.2) vs 8.3 months (95% CI, 7.3-9.1) with topotecan (n = 232) in the intention-to-treat (ITT) population (HR, 1.11; 95% CI, 0.90-1.37; stratified log-rank test, P = .3094), missing the primary end point of the study.

The median PFS by blinded independent central review (BICR) was 4.0 months (95% CI, 3.0-4.2) with liposomal irinotecan and 3.3 months (95% CI, 2.8-4.1) with topotecan in this population (HR, 0.96; 95% CI, 0.77-1.20; stratified log-rank test, P = .7053).

Notably, liposomal irinotecan elicited an objective response rate (ORR) of 44.1% (95% CI, 37.6%-50.8%) vs 21.6% (95% CI, 16.4%-27.4%), translating to a significant difference of 22.3% (95% CI, 14.0%-30.6%; P < .0001). Among those who responded to treatment in the investigative arm, 5.2% achieved a complete response (CR), 38.9% had a partial response (PR), and 29.7% had stable disease; 12.2% experienced disease progression.

“Although the primary end point of OS was not met, I think it’s interesting that liposomal irinotecan was associated with a substantially higher response rate, about double, compared with topotecan,” said Charles M. Rudin, MD, PhD, lead study author, chief of Thoracic Service, co-director of Druckenmiller Center of Lung Cancer Research, and Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering Cancer Center, in New York, New York, said in a presentation on the data. “I think the higher response rate together with the relative reduction in hematologic toxicity could support future combinatorial therapy research using liposomal irinotecan as a backbone.”

SCLC is a rapidly progressive tumor that represents approximately 15% of all lung cancers.^2,3 Liposomal encapsulation of irinotecan in a lipid-bilayer vesicle has been found to result in extended circulation and protection from hydrolysis as well as rapid metabolic conversion.⁴

Part 1 of RESILIENT was an open-label, dose-establishing, phase 2 study that enrolled 30 participants and had the key objective of identifying the optimal dose of liposomal irinotecan monotherapy. Investigators also sought to assess the early safety and efficacy of the product in these patients.

When liposomal irinotecan was administered at 70 mg/m2 (n = 25), it had encouraging antitumor activity with acceptable safety.⁵ Specifically, the agent elicited an ORR of 44.0% (95% CI, 24.40%-65.07%), which comprised 1 CR and 10 PRs. The median PFS was 3.98 months (95% CI, 1.45-4.24) and the median OS was 8.08 months (95% CI, 5.16-9.82). These data supported the FDA’s decision to grant a fast track designation to liposomal irinotecan as a second-line treatment for patients with SCLC in November 2020.⁶

Part 2, the randomized, open-label, phase 3 study, enrolled 461 patients with histologically or cytologically confirmed SCLC who had radiologically confirmed disease progression following frontline platinum-based chemotherapy and an ECOG performance status of 0 or 1.1

Participants were randomly assigned 1:1 to receive intravenous (IV) liposomal irinotecan at 70 mg/m2 every 2 weeks as part of 6-week cycles or IV topotecan at 1.5 mg/m2 for 5 days every 3 weeks as part of 6-week cycles. Treatment was continued until progressive disease or intolerable toxicity.

Key stratification factors included region, platinum sensitivity, performance status, and prior immunotherapy.

In addition to OS serving as the primary end point of the study, PFS and ORR per BICR represented the key secondary end points.

In the ITT population, the mean age was 62.3 years. Moreover, 32.1% of patients were women and 79.4% were White. Regarding ECOG performance status, 25.6% had a status of 0 and 74.2% had a status of 1. Most patients (88.7%) had metastatic disease and the remainder (11.3%) had locally advanced disease. Metastatic sites included the brain and/or the central nervous system (28.6%), hepatic (6.9%), and the bone and locomotor (23.6%). Previous treatment included radiotherapy (51.0%), immunotherapy (18.4%), and targeted therapy (0.4%).

A total of 226 patients in the liposomal irinotecan arm and 223 patients in the topotecan arm received treatment. In the investigative arm, 95.6% of patients discontinued treatment. The most common reason for doing so was disease progression (65.1%) followed by toxicity (10.0%), death (6.6%), or other (14.0%). A total 3.1% of patients were still receiving treatment at the time of data cutoff, which was February 8, 2022.

At the meeting, Rudin presented data from part 2 of the trial, which had a median follow-up of 18.2 months.

“[When] looking at a subgroup analysis of OS to try to tease out whether there are subgroups that selectively benefit, I would say overall, in my opinion, there’s really no group that stands out,” Rudin noted. “[Regarding] the [patients with] locally advanced [disease,] I would caution that [they] are few in number on this trial; I wouldn’t make much of that apparent difference [in benefit].”

The median duration of response with liposomal irinotecan was 4.1 months (95% CI, 3.1-4.3) vs 4.2 months (95% CI, 2.9-4.8) with topotecan.

A total of 449 patients comprised the safety population; this included 226 of those who received liposomal irinotecan and 223 of patients who were given topotecan.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 96.0% of those in the investigative arm and 99.1% of those in the control arm; any-grade treatment-related toxicities were observed in 86.3% and 96.0% of patients, respectively. Grade 3 or higher TEAEs were experienced by 62.4% of those who received liposomal irinotecan and 87.9% of those who were given topotecan. Serious TEAEs occurred in 46.5% and 39.5% of patients, respectively.

TEAEs resulted in dose reductions for 27.9% of those on the investigative arm and 46.6% of those on the control arm; TEAEs led to treatment discontinuation for 10.6% and 10.3% of patients, respectively. Moreover, 8.4% of those in the liposomal irinotecan arm had a TEAE that led to death vs 4.0% of those in the topotecan arm.

The most common grade 3 or higher TEAEs observed in the investigative and control arms, respectively, included diarrhea (13.7% vs 1.3%), neutropenia (8.0% vs 51.6%), decreased neutrophil count (4.4% vs 17.5%), leukopenia (4.0% vs 29.1%), decreased white blood cell count (4.0% vs 10.8%), anemia (2.7% vs 30.9%), decreased platelet count (1.3% vs 17.5%), and thrombocytopenia (0.4% vs 29.1%).

“The safety profile of liposomal irinotecan is consistent with its prior known safety profile, and no new safety concerns were identified,” Rudin concluded.

References

1. Rudin CM, Dowlati A, Chen Y, et al. RESILIENT part 2: a randomized, open-label phase 3 study of liposomal irinotecan versus topotecan in adults with relapsed SCLC. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 161O.
2. Byers LA, Rudin CM. Small cell lung cancer: where do we go from here? Cancer. 2015;121(5):664-672. doi:10.1002/cncr.29098
3. Zhong YJ, Wen YF, Wong HM, et al. Trends and patterns of disparities in burden of lung cancer in the United States, 1974-2015. Front Oncol. 2019;9:404. doi:10.3389/fonc.2019.00404
4. Drummond DC, Noble CO, Guo Z, et al. Development of highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Cancer Res. 2006;66(6):3271-3277. doi:10.1158/0008-5472.CAN-05-04007
5. Paz-Ares L, Spigel DR, Chen Y, et al. RESILIENT part 1: a phase 2 dose-exploration and dose-expansion study of second-line liposomal irinotecan in adults with small cell lung cancer. Cancer. 2022;128(9):1801-1811. doi:10.1002/cncr.34123
6. Ipsen receives FDA fast track designation for investigational irinotecan liposome injection (Onivyde) as a second-line monotherapy treatment for small cell lung cancer (SCLC). News release. Ipsen. November 30, 2020. Accessed April 5, 2023. https://www.ipsen.com/press-releases/