Hochmair, Maximilian Johannes

Abstract Introduction We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks. Methods Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment. Results In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; grade ≥ 3: 147 [26.8%]). Gastrointestinal and hepatic TRAEs, including diarrhea (171 [31.1%]), nausea (80 [14.6%]), elevated alanine aminotransferase (ALT; 68 [12.4%]), and elevated aspartate aminotransferase (AST; 67 [12.2%]) were the most common (≥10%). Dose interruption and dose reduction of sotorasib resulted in the resolution of >90% of diarrhea events; median time to resolution were 18.0 days and 22.0 days, respectively. Similar trends were observed for elevated ALT and AST events. Patients who stopped immunotherapy <3 months before initiating sotorasib had a higher incidence of treatment-related hepatotoxicity (80/240 [33.3%]) than those who stopped immunotherapy ≥3 months before initiating sotorasib (26/188 [13.8%]). Treatment-related pneumonitis/interstitial lung disease (ILD) and corrected QT (QTc) prolongation were observed in 9 (1.6%) and 4 (0.7%) patients, respectively. Two (0.4%) patients died with TRAEs, 1 with ILD whose ultimate cause of death was disease progression, and the other with an unknown cause. Conclusions Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose modification.

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.

e20502 Background: The CNS is often a site of first disease progression in CRZ-treated ALK+ NSCLC. The ALTA trial is assessing BRG, an investigational next-generation ALK inhibitor, in pts with CRZ-refractory advanced ALK+ NSCLC, including pts with baseline brain metastases. Methods: In ALTA (NCT02094573), pts were stratified by presence of baseline brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Here, we show data for pts with baseline brain metastases. An independent review committee (IRC) assessed intracranial efficacy. Results: Of 222 pts (112 in arm A; 110 in arm B), 80 (71%)/74 (67%) in A/B had baseline brain metastases per investigators, with median age 49/55 y; 74%/76% had received chemotherapy. As of May 31, 2016, 51%/59% of these pts continued to receive BRG in A/B; median follow-up was 9.6/11.4 mo. Intracranial efficacy is shown in the table. Among these pts, most common treatment-emergent adverse events were: nausea 35%/46% (A/B), headache 30%/31%, vomiting 29%/31%, diarrhea 21%/38%, cough 25%/32%; grade ≥3: increased blood CPK 1%/12%, hypertension 4%/7%, increased lipase 4%/3%. Conclusions: BRG yielded substantial intracranial responses with robust iPFS and acceptable safety in ALK+ NSCLC pts with baseline brain metastases in ALTA. 180 mg (with lead-in) showed consistently improved intracranial efficacy compared with 90 mg. Clinical trial information: NCT02094573. [Table: see text]