Epigenetic dysregulation contributes to cancer progression and resistance to treatment. Some data suggest that the kinetics of response to epigenetic drugs (ED) may differ from conventional chemotherapy. Investigating whether this operates in ED phase I (P1) trials is crucial, in order to avoid stopping prematurely an efficient treatment. Here, we assessed the kinetics and prognostic factors of response in patients (pts) enrolled in an ED P1 trial.
All consecutive pts with solid tumors or lymphoma, enrolled in a P1 trial evaluating an ED as monotherapy at the Gustave Roussy Drug Development Department between Jan 2010 and Jun 2020 were included. Pts and trial characteristics, response to treatment and outcome were retrospectively collected. Statistical associations were tested using a Fisher’s exact test and survival distributions were compared using the log-rank test.
Overall, 290 pts (median age of 60 yo, 61% male, 67% with solid tumors, median of 3 previous lines of therapy) enrolled in 22 ED monotherapy P1 trials were included. Median duration of treatment, progression free survival (PFS) and overall survival (OS) were 2.3, 2.1 and 10.1 months (mo), respectively. Disease control rate (DCR) was 52% and overall response rate (ORR) was 11% (32 pts). Median time to response was 2.3 mo (0.7-7.2); 53% of responses occurred at the first evaluation, 19% at the second and 28% beyond. Median duration of response was 4.6 mo (0.4-71.3). Baseline lactate dehydrogenase (LDH) < upper normal limit normal (p<0.001), RMH score 0-1 (p=0.01), GRIm score 0-1 (p=0.029) and absence of liver metastasis (p=0.02) were significantly associated with better DCR, but not ORR. A ≥ 25% increase of baseline LDH at C2D1 was associated with shorter PFS (1.3 vs 3.0 mo, p<0.001) and shorter OS (4.3 vs 13.7 mo, p<0.001), while a ≥ 25% decrease was associated with higher ORR (OR=6.57; 95% CI 2.35-17.95, p<0.001). The association between changes in tumor growth rate and outcome will be available at the time of the congress.
In ED phase I trials, nearly 50% of responses occurred beyond the first evaluation. Baseline LDH, GRIm and RMH scores are predictive of DCR but not ORR, whereas a ≥ 25% LDH variations at C2D1 correlated with responses.
Gustave Roussy Institute.
Has not received any funding.
J-M. Michot: Non-remunerated activity/ies: Amgen; Non-remunerated activity/ies: Astex; Non-remunerated activity/ies: AstraZeneca; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: Roche; Non-remunerated activity/ies: Sanofi; Non-remunerated activity/ies: Xenecor. L. Verlingue: Honoraria (self): Adaptherapy. V. Ribrag: Advisory/Consultancy, Research grant/Funding (self), Non-remunerated activity/ies: Epizyme; Research grant/Funding (self): ArgenX; Advisory/Consultancy, Non-remunerated activity/ies: Servier; Advisory/Consultancy: NanoString; Advisory/Consultancy: Gilead; Advisory/Consultancy: PharmaMar; Advisory/Consultancy: BMS; Advisory/Consultancy: MSD; Advisory/Consultancy: Incyte; Advisory/Consultancy: Roche; Advisory/Consultancy: Infinity. J-C. Soria: Shareholder/Stockholder/Stock options, Full/Part-time employment, Sept 2017-Dec 2019: AstraZeneca; Officer/Board of Directors: Hookpipa; Shareholder/Stockholder/Stock options: Daiichi Sankyo; Shareholder/Stockholder/Stock options: Gritstone. C. Massard: Non-remunerated activity/ies: Amgen; Non-remunerated activity/ies: Kusajili; Non-remunerated activity/ies: GSK; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: PharmaMar. S. Postel-Vinay: Research grant/Funding (self), Non-remunerated activity/ies: Boehringer Ingelheim; Research grant/Funding (self), Non-remunerated activity/ies: AstraZeneca; Research grant/Funding (self): Roche; Research grant/Funding (self): Merck; Non-remunerated activity/ies: Archimaid. All other authors have declared no conflicts of interest.