Abstract CT085: Safety of pemetrexed (Pem) plus platinum (Plat) in combination with pembrolizumab (Pembro) for metastatic nonsquamous NSCLC: A post hoc analysis of KEYNOTE-189
Authors: Garon Edward B. , Sun Fangfang , Muehlenbein Catherine E. , Kim Jong S. , Gadgeel Shirish M. 
Published: September 2020

Abstract
Background: Pem + Pembro and Plat prolonged overall survival (OS) and progression free survival (PFS) for metastatic nonsquamous NSCLC. In order to assess the safety of the combination, we evaluated time to onset and resolution of Grade 3-5 adverse events (AEs) and subsequent treatment discontinuation in patients receiving Pem+Plat+Pembro or Placebo.
Methods: The all-subjects-as-treated (ASaT) population in KEYNOTE-189 was analyzed. The data cut-off date was Nov 8, 2017. AEs of any cause were identified by system organ class and preferred term (MedDRA 20.1). Median and interquartile ranges for time to onset, resolution, and discontinuation due to AE were described.
Results: A total of 607 pts (405 vs. 202; Pembro arm vs. Placebo arm) were included. Median age was 64 years, 72% received carboplatin, and 18% had a history of brain metastases at baseline. Median treatment duration was 7.4 and 5.4 months in the Pembro and Placebo arms, respectively. Grade 3-5 AEs occurred in 272 (67.2%) and 133 (65.8%) patients in each arm, respectively. Onset and resolution times for AEs with ≥2% incidence are summarized (table). Among these, the median time to first occurrence was shortest (6 days) for nausea and longest (125 days) for pneumonitis. Median time from onset to resolution for resolved AEs ranged from 4 days (vomiting) to 25 days (pneumonitis and anemia). A total of 112 (27.7%) pts and 30 (14.8%) pts, respectively, discontinued any study drug due to AEs in each arm. 33% and 40% of the discontinuations for pemetrexed or pembrolizumab due to AEs occurred during cycles 1-4. Pem was discontinued due to AEs at a comparable rate when combined with Pembro vs Plac (2.0% vs 1.4% on average per cycle, respectively).
AEs with &gt;2% incidencePembro + Pem + Plat (N=405)Placebo + Pem + Plat (N=202)Grade 3-5 AEs of any cause *n (%)Median time (days) to first occurrence† (IQR Q1-Q3)Median time (days) to resolution (IQR Q1-Q3)n (%)Median time (days) to first occurrence† (IQR Q1-Q3)Median time (days) to resolution (IQR Q1-Q3)HematologicAnemia66 (16)60.5 (21 - 91)11 (7 - 21)31 (15)41 (20 - 78)21 (8 - 79)Neutropenia64 (16)52 (29 - 84)9 (7 - 14)24 (12)56 (26 - 84)8 (7 - 14)Thrombocytopenia32 (7.9)69 (32 - 95)12 (9 - 17)14 (6.9)49 (33 - 90)9 (8 - 14)Febrile neutropenia27 (6.7)54 (14 - 146)6 (4 - 8)4 (2.0)34 (22 - 80)4 (4 - 14)Non-hematologicAsthenia25 (6.2)68 (24 - 142)11 (5 - 28)7 (3.5)57 (13 - 147)1Fatigue23 (5.7)44 (5 - 147)11 (5 - 38)5 (2.5)91 (20 - 156)128Diarrhea21 (5.2)49 (28 - 150)7 (3-16)6 (3.0)39 (27 - 58)7 (6 - 9)Vomiting15 (3.7)31 (8 - 78)4 (3 - 12)6 (3.0)29 (5 - 58)7 (4 - 11)Nausea14 (3.5)6 (2 - 28)9 (5 - 15)7 (3.5)58 (7 - 132)7 (7 - 12)Pneumonitis11 (2.7)125 (76 - 149)25 (21 - 46)4 (2.0)83 (19 - 141)19 (14 - 25)Acute kidney injury8 (2.0)78 (31 - 159)240 (0)N/AN/AAE, Adverse event; IQR, Interquartile range, N/A, not applicable. AEs occurring &gt;2% are shown. *Grade 5 events reported for pneumonitis and acute kidney injury. †Time from the randomization to the first Grade 3-5 AE.
Conclusions: Most AEs first occurred within 3 months from the first study treatment administered and resolved within 2 weeks from the onset. Pembro+Pem+Plat is safe with manageable toxicity in long term use.
Citation Format: Edward B. Garon, Fangfang Sun, Catherine E. Muehlenbein, Jong S. Kim, Shirish M. Gadgeel. Safety of pemetrexed (Pem) plus platinum (Plat) in combination with pembrolizumab (Pembro) for metastatic nonsquamous NSCLC: A post hoc analysis of KEYNOTE-189 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT085.