Johnson, Melissa L.

519 Background: KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS mutations occur in approximately 90% of pancreatic cancer, and approximately 2% of these are KRASG12C mutations. Adagrasib, an investigational agent, is a KRASG12C inhibitor that irreversibly and selectively binds KRASG12C, locking it in its inactive state; adagrasib has been optimized for favorable pharmacokinetic (PK) properties, including long half-life (̃24 h), extensive tissue distribution, dose-dependent PK, as well as CNS penetration. Methods: KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy or in combinations in pts with advanced solid tumors harboring a KRASG12C mutation. Here we report preliminary data from pts enrolled in a Phase 2 cohort evaluating single-agent adagrasib administered orally at 600 mg BID in previously treated pts with unresectable or metastatic solid tumors (excluding NSCLC and CRC), including pancreatic and other GI cancers. Study endpoints include clinical activity, safety, and PK. Results: The data cutoff was 10 September 2021. A total of 42 pts were enrolled in this cohort (median age 63.5 years, range 21–89; 52% female; 71% white; 29%/71% ECOG PS 0/1; median 2 prior lines of therapy, range 1–7; median follow-up 6.3 months), of whom 30 pts had KRASG12C-mutant GI tumors (12 PDAC, 8 biliary tract, 5 appendiceal, 2 gastro-esophageal junction, 2 small bowel, and 1 esophageal). In a preliminary analysis, 27 pts with GI tumors were evaluable for clinical activity; partial responses (PRs) were seen in 41% (11/27, including 3 unconfirmed PRs); the disease control rate (DCR) was 100% (27/27). Of the 12 pts with PDAC (median 3 prior lines of therapy; median follow-up 8.1 months), 10 were evaluable for clinical activity; PRs were seen in 50% (5/10, including 1 unconfirmed PR); the DCR was 100% (10/10). Median progression-free survival (PFS) was 6.6 months (95% CI 1.0–9.7), and treatment was ongoing in 50% of pts with PDAC. Among the 17 evaluable pts with other GI tumors, 6 achieved PR (35%; 2 unconfirmed) with a DCR of 100% (17/17); 11 pts were still receiving treatment. In the overall cohort, treatment-related adverse events of any grade occurred in 91% (38/42), the most frequent being nausea (48%), diarrhea (43%), vomiting (43%), and fatigue (29%); grade 3/4 events occurred in 21% of pts, with no grade 5 events. Conclusions: Adagrasib monotherapy is well tolerated and demonstrates encouraging clinical activity in pretreated pts with PDAC and other GI tumors harboring a KRASG12C mutation. Further exploration of adagrasib is ongoing in this pt population (NCT03785249). Clinical trial information: NCT03785249.

TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.

Abstract Background Platinum chemotherapy (carboplatin or cisplatin) + etoposide is the current 1L standard of care treatment (tx) for ES-SCLC. Despite high response rates on this regimen, patient (pt) outcomes remain poor. IMpower133 is a Ph1/3, double-blind, randomized, placebo (PBO)-controlled trial that is evaluating the efficacy and safety of adding PD-L1-inhibitor atezo or PBO to 1L tx for ES-SCLC (NCT02763579). Methods IMpower133 enrolled pts without prior tx for ES-SCLC; PD-L1 testing was not required. Pts were randomized 1:1 to four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) + etoposide (100 mg/m2 IV, Days 1-3) with either atezo (1200 mg IV, Day 1) or PBO, then maintenance atezo or PBO until PD, unacceptable toxicity or loss of clinical benefit. Maintenance prophylactic cranial irradiation (PCI) was allowed per protocol, while definitive thoracic radiation (TR) was not. Coprimary endpoints were OS and investigator-assessed PFS. A key exploratory endpoint was outcomes by blood tumor mutation burden (bTMB) analyzed at prespecified cutoffs (≥ 16 vs < 16 and ≥ 10 vs < 10 mutations/Mb). Results Adding atezo to carboplatin + etoposide demonstrated significant improvement in efficacy (OS and PFS) in 1L ES-SCLC (Table). Survival benefits were consistent across key subgroups and prespecified bTMB cutoffs. 44 pts (22 in each arm [per ITT]) received PCI, and 7 (3 in atezo arm, 4 in PBO arm) received TR. Gr 3-4 tx-related adverse events (AEs) occurred in 57% of atezo pts vs 56% of PBO pts; serious tx-related AEs occurred in 23% vs 19%. Occurrence of CNS-related AEs in pts who had PCI are shown in the Table. Conclusion Adding atezo to carboplatin + etoposide resulted in a significant improvement in survival in this 1L ES-SCLC all-comers population. There were no new safety signals, including in pts who received PCI or TR. Atezo + carboplatin + etoposide may represent a new standard regimen for untreated ES-SCLC. Atezo + carboplatin + etoposiden = 201PBO + carboplatin + etoposiden = 202Co-primary endpointsMedian OS, mo12.310.3HR 0.70 (95% CI: 0.54, 0.91); P = 0.0069Median PFS, mo5.24.3HR 0.77 (95% CI: 0.62, 0.96) P = 0.017Secondary efficacy endpointsInvestigator-assessed confirmed ORR, %60.264.4Median DoR, mo4.23.9CNS-related AEs in pts who had PCI, n (%)a,bn = 23n = 21Headache8 (34.8)4 (19.0)Asthenia5 (21.7)2 (9.5)Dizziness2 (8.7)0Insomnia2 (8.7)1 (4.8)Fall2 (8.7)1 (4.8)aSafety population; safety analyses conducted according to tx received (1 pt randomized to the control arm received a dose of atezo).bIncludes AEs occurring in ≥ 2 patients. Citation Format: Aaron S. Mansfield, Stephen V. Liu, Aleksandra Szczęsna, Libor Havel, Maciej Kzrakowski, Maximilian J. Hochmair, Florian Huemer, György Losonczy, Melissa L. Johnson, Makoto Nishio, Martin Reck, Tony S. Mok, Sivuonthanh Lam, David S. Shames, Juan Liu, Fairooz Kabbinavar, Alan Sandler, Leora Horn. IMpower133: Primary efficacy and safety + CNS-related adverse events in a Ph1/3 study of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT199.