Abstract 476P
Background
Single agent SEL, an oral selective inhibitor of nuclear export (SINE), has shown activity against CRC with RAS mutations (mut) or wildtype (wt) in clinical studies. In preclinical studies SEL upregulated immune function and sensitized tumors to PD-1/PD-L1 blockade. A phase Ib study (NCT02419495) showed the safety and antitumor activity of combined SEL and a PD-1/PD-L1 inhibitor. This study aims to evaluate combined SEL with pembro in patients (pts) with chemotherapy refractory CRC.
Methods
This phase I/II, open-label study enrolled pts with advanced/metastatic CRC that progressed after prior chemotherapy (1-3 lines for RAS wt, 1-2 for RAS mut). Pts were treated using weekly oral SEL 80 mg and pembro 200 mg IV every 3 weeks. Antitumor activity, safety and tolerability were assessed.
Results
Enrollment has been completed. Thirty pts, median age 57.5 years, male 63%, RAS mut 53%, median prior lines 2, are enrolled. At data cutoff (31-MAR-21) median treatment duration was 57 days (range: 1-246) and 24 pts were evaluable for response. Best response was stable disease in 11 pts (8 [73%] have RAS mut CRC) and progressive disease (PD) in 13 (8 [62%] have RAS wt CRC). Median progression-free survival is 12.9 and 7.1 weeks for pts with CRC with RAS mut and wt, respectively (p=0.20). Median overall survival has not been reached for pts with CRC with RAS mut and is 6.1 months for those with RAS wt (p=0.09). Twenty-five pts (83%) discontinued therapy, mostly due to PD. One pt died and another discontinued due to a treatment-emergent adverse event (TEAE). The most common TEAEs (total; Grade ≥3) were nausea (77%; 0%), vomiting (43%; 0%), fatigue (43%; 13%), decreased appetite (37%; 0%), diarrhea (37%; 0%). Eight pts (27%) had 9 serious TEAEs.
Conclusions
Combined SEL with pembro demonstrated disease control in pts with chemotherapy refractory advanced/metastatic CRC, that would not have been otherwise eligible for pembro because their tumors were not MSI-H. Disease control was greater among pts with RAS mut versus wt tumors. Therapy was well tolerated with no unanticipated AEs. Further investigation of this combined treatment is warranted, particularly in pts with CRC with RAS mut.
Clinical trial identification
NCT04256707.
Editorial acknowledgement
Legal entity responsible for the study
Karyopharm Therapeutics Inc.
Funding
Karyopharm Therapeutics Inc.
Disclosure
T. Golan: Financial Interests, Personal, Advisory Board: AstraZeneca; AbbVie; Teva; Bayer; Merck MSD; Financial Interests, Personal, Invited Speaker: Bioline; Roche; Financial Interests, Institutional, Other, Grant: AstraZeneca; Merck MSD. R. Geva: Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Lilly; Medison; Roche; Novartis; Janssen; Takeda; Merck Sharp & Dohme; Pfizer; Merck; Financial Interests, Personal, Advisory Role: Eisai; AstraZeneca; Bayer; Merck Sharp & Dohme; Novartis; Boehringer Ingelheim; BOL Pharma; Roche; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Personal, Other, Travel expenses & accommodations: Merck; Financial Interests, Personal, Other, Travel expenses & accommodations: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel expenses & accommodations: Bayer; Financial Interests, Personal, Other, Travel expenses & accommodations: Medison; Financial Interests, Personal, Leadership Role: Pyxis; Financial Interests, Personal, Stocks/Shares: Pyxis; Financial Interests, Personal, Stocks/Shares: BOL Pharma. A. Zick: Financial Interests, Institutional, Research Grant: Karyopharm Therapeutics Inc.; Merck; Roche. E. Netiv: Financial Interests, Personal, Full or part-time Employment: Karyopharm therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc..F. Yang: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc.i.S. Sharoni: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc..C. Meng: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc..P. Duic: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc..D. Michel: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc..E. Sbar: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Stocks/Shares: Merck Sharp & Dohme. J. Shah: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc.. M.G. Kauffman: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc.. S. Shacham: Financial Interests, Personal, Full or part-time Employment: Karyopharm Therapeutics Inc.; Financial Interests, Personal, Stocks/Shares: Karyopharm Therapeutics Inc.. A. Zer: Financial Interests, Personal, Invited Speaker: Roche; Bristol Myers Squibb; Merck Sharp & Dohme; Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Stocks/Shares: Nixio; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb.All other authors have declared no conflicts of interest.