M. Dómine Gómez

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

The combination of adagrasib (ada), a KRASG12C inhibitor, with an immune checkpoint inhibitor (CPI) has demonstrated enhanced preclinical anti-tumor activity. We report safety and efficacy of ada + pembrolizumab (pembro) in patients (pts) enrolled in the KRYSTAL-1 (NCT03785249) and KRYSTAL-7 (NCT04613596) trials. In a Ph 1b cohort of KRYSTAL-1 and Ph 2 KRYSTAL-7, pts with treatment-naïve, KRASG12C-mutated, advanced NSCLC received concurrent ada 400 mg BID + pembro 200 mg Q3W. Pts were enrolled across all PD-L1 levels. Endpoints were safety and efficacy (objective response rate [ORR], duration of response [DOR], progression-free survival [PFS], overall survival [OS]). As of 30 Aug 2022, 75 pts (median follow-up 3.5 mo) had received ada + pembro in KRYSTAL-7 and were safety evaluable. Median age was 66 yrs, 51% were female, 35%/65% were ECOG PS 0/1. Any grade treatment-related adverse events (TRAEs) occurred in 83% of pts; most common were nausea (48%), diarrhea (43%) and vomiting (24%). Grade 3–4 TRAEs occurred in 44% of pts; most common were increased lipase (11%) and increased ALT/AST (8%/9%), all Grade 3. There were no Grade 5 TRAEs. TRAEs led to both ada and pembro discontinuation in 3% of pts. In a preliminary analysis of tumor response among 53 pts with at least 1 on-study scan (median treatment duration 2 mo), ORR was 49% (26/53 [5 uPR]) and disease control rate (DCR) was 89%; 6 pts had responses on the second on-study scan or later and ORR was 56% in pts enrolled ≥6 mo before data cut-off. DOR, PFS, and OS were not mature, with most pts still on treatment. In KRYSTAL-1, 7 pts (median follow-up 19.3 mo) were clinically evaluable. ORR was 57% (4/7), DCR was 100%; treatment was ongoing >18 months in 2 responders. Safety was consistent with KRYSTAL-7. Additional analyses will be presented. In the largest dataset evaluating a KRASG12C inhibitor combined with a CPI as first-line treatment for NSCLC presented to date, concurrent ada 400 mg BID in combination with pembro had manageable toxicity and demonstrated encouraging preliminary efficacy.