Citations

Abstract Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2–7.6). Median progression-free survival was 6.9 months (95% CI, 5.7–7.4) and median overall survival was 15.9 months (95% CI, 11.8–18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3–4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance. Significance: Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer. This article is featured in Selected Articles from This Issue, p. 897 See co-corresponding author Rona Yaeger discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932606282/f27a6e46f4

434 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor with unique binding properties to FGFR, potently inhibited FGFR2 fusion/rearrangement and acquired resistant mutations in pre-clinical models and in phase I trials that included cholangiocarcinoma (CCA) patients (pts). Here we present the efficacy and safety of tinengotinib in a phase II clinical trial. Methods: Eligible pts with advanced/metastatic CCA who had received ≥ 1 prior systemic chemotherapy therapy and ECOG PS 0 or 1 were treated with tinengotinib 10 mg QD. Four cohorts included: Cohort A1: FGFR2 fusion(s) with primary progression on previous FGFR inhibitor ( FGFRi), A2: FGFR2 fusion(s) with progression after prior response to FGFRi (acquired resistance); B: non-fusion FGFR alteration(s): C: FGFR wild-type ( FGFRwt). Primary endpoint was objective response rate (ORR) per RECIST v1.1. CTCAE V5.0 was used for safety assessments. Results: As of 7Aug2023, 48 pts with CCA were enrolled, 13 in Cohort A1, 10 in A2, 12 in B, 13 in C. Median age 61.5 [range 25-81] years old, 41.7% male, 58.3% had ≥ 3 lines of prior therapy. ECOG PS 0 in 47.9% pts. Among 35 pts with FGFR alterations, 80.0% had ≥ 1 prior FGFRi therapy, and 97.1% had prior chemotherapy. Forty (40) pts were efficacy evaluable. In A1, 1 out of 11 pts (9.1%) achieved PR with tumor reduction of 31.8%. In A2, 3 out of 8 pts (37.5%) achieved PR with tumor reduction of 40.7%, 47.0% and 54.6%. In B, 3 out of 9 pts (33.3%) achieved PR with tumor reduction of 36.5%, 48.6%, and 60.6%. No PR was observed in C. Overall DCR was 94.7% (18/19) in FGFR2 fusion/rearrangement pts (A1+A2), 88.9% (8/9) in other FGFR alterations pts (B), and 75% (9/12) in FGFRwt pts (C). Median progression-free survival (mPFS) was 5.26 months (95%CI, 2.86-9.10) in A1+A2, 5.98 months (95%CI, 1.87-NA) in B and 3.84 months (95% CI, 1.84-4.80) in C. Among 48 treated pts, treatment-related AEs (TRAEs) occurred in 45 (93.8%) pts, 14 (29.2%) in G1-2, 29 (60.4%) in G3 and 2 (4.2%) in G4. The most common G3 TRAEs were hypertension in 12 (25%), palmar-plantar erythrodysesthesia syndrome in 3 (6.3%), diarrhea in 3 (6.3%) and stomatitis in 3 (6.3%). One subject had G4 increased TSH and G4 increased lipase, and another subject had G4 posterior reversible encephalopathy syndrome. No G5 TRAE was observed. Conclusions: Tinengotinib has promising clinical benefit for FGFR2 fusion CCA after prior FGFRi and for non-fusion FGFR alterations. Tinengotinib-related toxicities were manageable. An ongoing randomized, controlled phase III study will evaluate the clinical efficacy, safety, and pharmacodynamic effect of Tinengotinib vs Physicians’ choice in subjects with FGFR2-altered refractory/relapsed CCA after prior chemotherapy and FGFRi therapy. Clinical trial information: NCT04919642 .

3083 Background: Cancer-Specific Plectin (CSP) is a novel pro-tumorigenic target that is selectively expressed on the surface of tumors, while absent from benign tissue. CSP is highly expressed in many solid cancers, particularly pancreatic (PC), cholangiocarcinoma (CCA), and ovarian (OC). ZB131 (Zielbio), is a humanized anti-CSP IgG1 monoclonal antibody that binds specifically to CSP on the surface of tumor cells, rapidly internalizes and modulates key proliferative and cytoskeletal remodeling signaling pathways to decrease cancer cell growth and increase the recruitment of anti-tumor immune infiltrates. Methods: The dose escalation (3+3 design) and expansion are enrolling adult patients (pts) with advanced treatment-refractory solid tumors. ZB131 was administered IV over 60 minutes (without premedication) weekly. The starting dose of ZB131 is 0.3 mg/kg followed by 1,3, 9, 15 and 30 mg/kg. Primary objectives are safety, tolerability, and maximum tolerated dose/determination of Phase 2 dose. Secondary objectives are preliminary efficacy (RECIST v1.1), Pharmacokinetic (PK) and pharmacodynamic parameters in blood and paired tumor biopsies. Results: As of 31 Jan 2023, 24 pts had enrolled (9 PC, 6 CCA, 4 OC, 5 other). The median age was 59.5 yr (range, 35 – 84) with a median of 4 prior lines of therapy. The median ZB131 treatment duration is 5.3 weeks (range, 1 – 33). No dose-limiting toxicities were observed up to the dose of 30 mg/kg which is currently enrolling. Treatment-related adverse events (TRAEs) were grade 1/ 2: nausea (n=6), fatigue (n=5), anemia (n=3), diarrhea (n=2), flulike symptoms (n=2), and vomiting (n=2). Mild flu-like symptoms and nausea/vomiting were observed during or following infusion at doses of 9 mg/kg and above. Except for one episode of Gr 3 neutropenia at the 30 mg/kg dose, no other drug-related grade 3/4 TRAE’s were reported. Five pts had stable disease range, 12 – 33 weeks (2 PC, 1 CCA, 2 OC), with a 43% decrease in CA-125 observed in one OC pt. The PKs are linear and dose-proportional for all dose levels evaluated (estimated T ½ of 6-9 days). No antidrug antibodies have been detected. Conclusions: Interim data from dose-escalation of this first-in-class, anti CSP antibody, demonstrates good tolerability with encouraging signs of activity and target engagement in heavily pretreated pts. Results support further clinical evaluation of ZB131 in dose-expansion cohorts including OC and including combination therapy with gemcitabine. Clinical trial information: NCT 05074472 .

PURPOSE Adagrasib, a KRAS G12C inhibitor, has demonstrated clinical activity in patients with KRAS G12C -mutated non–small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRAS G12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRAS G12C mutation. METHODS In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249 ; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRAS G12C -mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety. RESULTS As of October 1, 2022, 64 patients with KRAS G12C -mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. CONCLUSION Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRAS G12C -mutated solid tumors.

425082 Background: KRAS, a mediator of signalling pathways essential for cellular growth, proliferation, and survival, is the most frequently mutated oncogene in cancer. Notably, KRAS mutations occur in ~90% of pancreatic cancers, of which ~2% are KRASG12C mutations. Other gastrointestinal (GI) tumors also harbor KRASG12C mutations, such as biliary tract cancer (BTC; 1%) and appendiceal cancer (3–4%), and they are also seen in non-GI tumors, such as endometrial and ovarian cancer (1–2%). Adagrasib, a covalent KRASG12C inhibitor that irreversibly and selectively binds KRASG12C in its inactive state, was selected for favorable properties, including long half-life (23 h), dose-dependent pharmacokinetics, and central nervous system penetration. Methods: KRYSTAL-1 is a multicohort phase 1/2 study (NCT03785249) evaluating adagrasib in patients (pts) with advanced solid tumors harboring a KRASG12C mutation. Here we report data from a phase 2 cohort evaluating adagrasib monotherapy administered orally at 600 mg BID in pts with unresectable or metastatic KRASG12C-mutated solid tumors (excluding non-small cell lung cancer and colorectal cancer), including pancreatic ductal adenocarcinoma (PDAC), BTC, other GI, and non-GI tumors. Study objectives include evaluation of clinical activity (ORR, DCR, DOR, PFS, OS) and safety. Results: As of October 1, 2022, 64 pts with KRASG12C-mutated solid tumors were enrolled and 63 were treated with adagrasib (median follow-up, 16.8 months); of these, 21 pts had PDAC, 12 BTC, 16 other GI tumors (9 appendiceal, 4 gastro-esophageal junction/esophageal, 3 small bowel), and 14 non-GI tumors (5 ovarian, 4 unknown primary, 3 endometrial, 1 breast, 1 glioblastoma). Overall, median age was 65 years, 61% had ECOG PS 1, and median prior lines of systemic therapy was 2. Among 57 pts with measurable disease (blinded independent central review), ORR was 35.1% (20/57; all partial responses); DCR was 86.0% (49/57); median DOR was 5.3 months (n=20; 95% CI 2.8–7.3); median PFS was 7.4 months (95% CI 5.3–8.6); and median OS was 14.0 months (n=64; 95% CI 8.5–18.6). Among 21 pts with PDAC, ORR was 33.3% (7/21); DCR was 81.0% (17/21); median PFS was 5.4 months (95% CI 3.9–8.2); and median OS was 8.0 months (95% CI 5.2–11.8). Among 12 pts with BTC, ORR was 41.7% (5/12); DCR was 91.7% (11/12); median PFS was 8.6 months (95% CI 2.7–11.3); and median OS was 15.1 months (95% CI 8.6–not estimable). Overall (n=63), treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of pts (most commonly [≥20%] nausea [49.2%], diarrhea [47.6%], fatigue [41.3%], vomiting [39.7%]), grade 3 TRAEs in 25.4%, and grade 4 TRAEs in 1.6%. No grade 5 TRAE occurred. Conclusions: Adagrasib is well tolerated and demonstrates promising clinical activity in pretreated pts with PDAC, BTC, and other solid tumors harboring a KRASG12C mutation. Clinical trial information: NCT03785249 .