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Key Studies in Lung Cancer: Independent Conference Coverage of the World Conference on Lung Cancer 2020

Shirish M. Gadgeel, MD
Nicolas Girard, MD, PhD
Released: March 31, 2021

SCLC

Part 1 of Phase II RESILIENT Study of Liposomal Irinotecan in Postplatinum SCLC: Study Design

Shirish M. Gadgeel, MD:
The RESILIENT study is evaluating liposomal irinotecan, a drug that is currently approved for patients with recurrent pancreatic cancer, in patients with SCLC. Paz-Ares and colleagues31 reported data from part 1 of the phase II/III RESILIENT study of liposomal irinotecan at either 85 mg/m2 or 70 mg/m2 every 2 weeks in 30 patients 18 years of age or older who had progressed on previous platinum-based frontline therapy. The primary endpoints include safety/tolerability and recommended dose for part 2. Key secondary endpoints are ORR, PFS, and OS.

Part 1 of Phase II RESILIENT Study of Liposomal Irinotecan in Postplatinum SCLC: Efficacy

Shirish M. Gadgeel, MD:
This study showed an impressive ORR ranging between 40% and 44%. The median DoR was modest at 3.78 months for all patients and the median PFS was also relatively low at approximately 4 months. The median OS with the 70-mg/m2 dose was 8.08 months. Now, these data should be interpreted with caution given that the number of patients in this study is extremely small—only 30—but this level of response following platinum-based chemotherapy is quite promising.

Part 1 of Phase II RESILIENT Study of Liposomal Irinotecan in Postplatinum SCLC: Safety

Shirish M. Gadgeel, MD:
Notable grade ≥3 TRAE in all patients treated (N = 30) included diarrhea (26.7%), neutropenia (16.7%) anemia (6.7%), fatigue (6.7%), hypokalemia (6.7%), and hypomagnesemia (6.7%). All patients receiving the 85-mg/m2 dose and 70-mg/m2 dose experienced TEAEs. TEAEs led to dose reduction/discontinuation in 80%/20% and 28%/8% of patients receiving the 85-mg/m2 dose and 70-mg/m2 dose, respectively. Toxicities were as expected with this drug.

Part 1 of Phase II RESILIENT Study of Liposomal Irinotecan in Postplatinum SCLC: Conclusion

Shirish M. Gadgeel, MD:
Data presented at this meeting for the part 1 portion of a 2-part phase II/III study suggest liposomal irinotecan at the recommended dose of 70 mg/m2 exhibited favorable efficacy and safety profile in patients with relapsed SCLC. This novel delivery method of a topoisomerase inhibitor may improve on the toxicity profile of these agents. Thus, it will be interesting to see what the data will show for the ongoing phase III study portion evaluating liposomal irinotecan vs topotecan (NCT03088813).

Phase I/II Study of Lurbinectedin Plus Irinotecan in Relapsed SCLC: Study Design

Nicolas Girard, MD, PhD:
At WCLC 2020, Ponce-Aix and colleagues32 reported safety and efficacy data from a phase Ib/II study of lurbinectedin in combination with irinotecan in a cohort of 21 patients with advanced SCLC who had received at least 1 previous line of chemotherapy. Patients received lurbinectedin 2 mg/m2 on Day 1 plus irinotecan 75 mg/m2 on Day 1 and 8 plus granulocyte colony-stimulating factor (G-CSF). The primary endpoints of this study were identifying the maximum tolerated dose and recommended dose. Secondary endpoints included safety, pharmacokinetics, and efficacy.

Lurbinectedin was previously evaluated in combination with doxorubicin vs physician’s choice of topotecan or cyclophosphamide/doxorubicin/vincristine in the ATLANTIS study (NCT02566993), which failed to meet its primary endpoint of OS, based on a company press release. Despite the results from ATLANTIS, this study is interesting because preclinical data suggests lurbinectedin plus irinotecan have synergistic/additive antitumor activity when combined.

Phase I/II Study of Lurbinectedin Plus Irinotecan in Relapsed SCLC: Baseline Characteristics

Nicolas Girard, MD, PhD:
In this study, patients had a median age of 61 years and 80% had extensive-stage disease; 29% of patients were considered to have bulky disease, defined as 1 lesion >50 mm, and median sum of longest diameters was 86 mm (range: 19-180). Most (62%) patients had received 1 previous line of treatment and the median chemotherapy-free interval was approximately 3 months.

Phase I/II Study of Lurbinectedin Plus Irinotecan in Relapsed SCLC: Efficacy Summary

Nicolas Girard, MD, PhD:
The ORR in this very small study was 62% and the clinical benefit rate was 81%. The median PFS was 6.2 months and the median DoR was approximately 6.7 months, which is quite high in this patient population.

Phase I/II Study of Lurbinectedin Plus Irinotecan in Relapsed SCLC: Safety Summary

Nicolas Girard, MD, PhD:
The most common grade 3/4 TRAEs were neutropenia (62%), diarrhea (29%), fatigue (24%), and anemia (19%). TRAEs led to dose reductions in approximately 52% of patients; approximately 33% of patients required RBC transfusion to manage cytopenias this study. It is important to note that because neutropenia is an expected AE of these treatments, G-CSF support was incorporated into the design of this trial. We are familiar with the prevention and management of neutropenia, so the combination of lurbinectedin and irinotecan is of interest in relapsed advanced SCLC despite these manageable AEs.

Phase I/II Study of Lurbinectedin Plus Irinotecan in Relapsed SCLC: Conclusion

Nicolas Girard, MD, PhD:
Although the combination of lurbinectedin and irinotecan has some promising efficacy, with a response rate of 62% and median PFS a little more than 6 months, the combination remains quite toxic and treatment prophylaxis support with G-CSF should be considered in patients who are to be started on this experimental therapy in the setting of a clinical trial. This phase I/II study, in light of the negative phase III ATLANTIS study of lurbinectedin plus doxorubicin, showed that possibly the combination of lurbinectedin with irinotecan has better antitumor activity and should be further explored.

Phase I Dose-Exploration/Expansion Study of AMG 757 in Relapsed/Refractory SCLC: Study Design

Nicolas Girard, MD, PhD:
At the virtual WCLC 2020 annual meeting, we also saw data presented for AMG 757, which is a bispecific ADC targeting DLL3. DLL3 is a Notch ligand that is highly expressed in endocrine tumors including SCLC. Owonikoko and colleagues33 presented results from a phase I trial of AMG 757 in 52 patients with refractory SCLC who had received at least 1 previous platinum-based chemotherapy. Patients received AMG 757 doses ranging from 0.003 to 30 mg every 2 weeks. The primary endpoints included safety/tolerability and defining the maximum tolerated dose. Secondary endpoints included evaluating the pharmacokinetics and antitumor activity of this compound.

Phase I Dose-Exploration/Expansion Study of AMG 757 in Relapsed/Refractory SCLC: Baseline Characteristics

Nicolas Girard, MD, PhD:
The median age of patients enrolled on this study was 64 years; 96% of patients had extensive-stage disease at diagnosis, with a median of 2 previous therapies (range: 1-6) received. The percentage of patients with brain metastasis and liver metastasis was 25% and 48%, respectively.

Phase I Dose-Exploration/Expansion Study of AMG 757 in Relapsed/Refractory SCLC: Safety

Nicolas Girard, MD, PhD:
To me, the safety profile of AMG 757 was not particularly concerning. Cytokine-release syndrome (CRS) was reported in 44% of patients, but it was manageable with supportive care and corticosteroids. Most events of CRS were grade 1/2, and there were no grade 4/5 events of CRS on this study. This AE is part of the mechanism of action of bispecific antibodies and is probably associated with the efficacy, so this was expected. Only 1 patient discontinued due to treatment-related AE. There was 1 drug-limiting toxicity of pneumonitis that resulted in death.

Phase I Dose-Exploration/Expansion Study of AMG 757 in Relapsed/Refractory SCLC: Efficacy

Nicolas Girard, MD, PhD:
The confirmed response rate of 14% in this cohort of patients was quite high when compared with existing options in this disease setting. However, this needs further confirmation with additional follow-up. Overall, stable disease was reported for 22% of patients in this study.

Phase I Dose-Exploration/Expansion Study of AMG 757 in Relapsed/Refractory SCLC: DoR

Nicolas Girard, MD, PhD:
In patients with relapsed/refractory SCLC, the key unmet need is seeing prolonged efficacy with currently available treatment options. In this phase I study, AMG 757 showed prolonged efficacy, with 20% of patients completing ≥6 months of treatment and a median DoR of 6.2 months in patients with a confirmed response, which to me is the most striking result of this agent to date.

Phase I Dose-Exploration/Expansion Study of AMG 757 in Relapsed/Refractory SCLC: Conclusion

Nicolas Girard, MD, PhD:
Despite new combination chemotherapy plus immunotherapy treatment options in frontline for SCLC, we continue to have an unmet need in the second line setting for patients who relapse or become refractory to frontline therapy. Data from the early phase I study of AMG 757 are promising, with a safety profile that includes mostly low-grade CRS, which may be related to the mechanism of action for this agent, and confirmed PR responses of 14% and a median DoR of 6.2 months. These results are favorable when compared with our current treatment paradigm with topotecan, which is associated with very low efficacy.

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