Citations

Abstract Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. Results: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2–2.6] and 6.9 (95% CI, 5.7–8.4) months, respectively. Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

4009 Background: Oncogenic FGFR2 alterations (fusions/rearrangements (f/r), amplifications, mutations) represent a broad therapeutic opportunity as they drive multiple solid tumors, particularly cholangiocarcinoma (CCA). However, off-isoform toxicity and on-target resistance limit the benefit of approved pan-FGFR inhibitors (FGFRi). RLY-4008 is the first potent, highly selective, oral FGFR2 inhibitor designed to overcome these limitations by targeting FGFR2 driver alterations and resistance mutations. Here, we present updated dose escalation results from ReFocus (NCT04526106), a seamless Phase I/II, open label study evaluating the safety and preliminary efficacy of RLY-4008 in patients (pts) with advanced, FGFR2-altered solid tumors. Methods: Adult pts received RLY-4008 BID, QD, QD discontinuous on a 4-week (wk) cycle following a Bayesian Optimal Interval design. Treatment-related adverse events (TRAEs), PK, ctDNA and anti-tumor activity (RECIST v1.1) were assessed. Results: As of 30 Jan 23, 116 pts (82 f/r, 27 mutation, 6 amplification) received RLY-4008 at doses of 20-200 mg/day, including 91 with CCA. 50% had prior FGFRi, and median lines of prior therapies was 3 (1-15). 28/46 ct-DNA-evaluable pts with CCA with prior FGFRi had ≥1 baseline resistance mutation, most commonly at FGFR2 N549X (23/46) or V564X (17/46). RLY-4008 had favorable PK with doses ≥40 mg QD providing FGFR2 occupancy ≥90%. 70 mg QD was the RP2D based on PK, safety, anti-tumor activity and exposure-dependent tumor regressions in FGFRi-naïve CCA f/r pts. Anti-tumor activity was observed in CCA and solid tumors across doses and FGFR2 alterations with radiographic tumor reductions in 74 (64%), SD/PR in 83 (72%), including 4/4 (100%) FGFRi-naïve CCA f/r pts at RP2D achieving confirmed PR. Clinically meaningful disease control and durable responses were observed in pts with FGFR2 f/r CCA. Overall, median treatment duration was 24 wks (range <1-108 wks). 105 pts discontinued (PD (81%), AE (3%), other (7%)). Across doses, most common TRAEs were low-grade PPE (57%), stomatitis (56%), dry mouth (38%), alopecia (28%), and dry eye (22%). No grade 4/5 TRAEs were observed. Conclusions: These encouraging dose escalation data confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity. Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA. Clinical trial information: NCT04526106 . [Table: see text]

Abstract Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT018.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.

Abstract INTRODUCTION: Oncogenic FGFR2 alterations (fusions/rearrangements, amplifications, mutations) are key drivers in cholangiocarcinoma (CCA) and multiple solid tumors. Current pan-FGFR inhibitor (FGFRi) therapy is limited by off-isoform toxicity and acquired FGFR2 kinase domain resistance mutations. RLY-4008 is a highly selective and potent oral inhibitor designed to target both FGFR2 driver and resistance mutations. We initiated a first-in-human study in advanced solid tumors patients (pts) to define the safety, pharmacokinetics (PK) and efficacy of RLY-4008 (NCT04526106). METHODS: Adult pts received RLY-4008 QD or BID on a 4-week cycle following a BOIN escalation design. Adverse events (AEs), PK, ctDNA and anti-tumor activity (RECIST 1.1) were assessed. RESULTS: As of 16AUG21, 45 pts (35 CCA; 10 other) have been treated with RLY-4008 at total daily doses of 30-200 mg (18 pts BID; 27 pts QD). 44 pts had oncogenic FGFR2 alterations (26 fusions/13 mutations/5 amplifications). The median number of prior anti-neoplastic therapies was 3 (range 1-15). 94% (33/35) of CCA pts had prior chemotherapy and 69% (24/35) had prior FGFRi. 56% (9/16) CCA pts with prior FGFRi and evaluable ctDNA had ≥1 FGFR2 resistance mutation at baseline, most commonly at positions 549 (8/9), 617 (3/9), or 564 (2/9). RLY-4008 had rapid absorption (Tmax 1-7h), half-life to support QD dosing (18-34 h), dose-dependent exposure (AUC; Cmax) and predicted FGFR2 occupancy &gt;85% across dose levels. The MTD has not been defined, and QD dose exploration continues to select the optimal biologically efficacious dose. AEs occurring in &gt;20% of pts include stomatitis (49%), palmar-plantar erythrodysesthesia (PPE, 38%), dry mouth (29%), and nail toxicities (22%), majority of which were ≤Gr 2. 6 pts had Gr 1-2 retinopathy, which resolved in all cases. 5 AEs were considered dose limiting toxicities: 4 in BID (rash/PPE/mucositis/hyperbilirubinemia) and 1 in QD (retinopathy). No Gr 4/5 drug-related AEs were seen. 25 pts remain on treatment (range 1-37 weeks). RLY-4008 showed broad anti-tumor activity across dose levels and FGFR2 alterations with radiographic tumor reductions of ≥10% in 59% pts (19/32; -11% to -83%). Activity was seen in FGFRi-naïve, FGFR2-fusion+ CCA with PRs in 50% of pts (3/6, 2 confirmed and 1 pending confirmation; -56% to -83%). Activity was also seen in FGFRi pre-treated FGFR2-fusion+ CCA pts (N=16) with 16 SD, including 9 pts with tumor reduction ≥10% (from -12% to -35%). Of the FGFRi pre-treated FGFR2-fusion+ CCA patients with detectable FGFR2 resistance mutations in ctDNA at baseline, 78% (7/9) were undetectable at C2D1. CONCLUSION: RLY-4008 demonstrates promising safety, tolerability, and clinical activity in FGFR2-altered solid tumor pts, including those who progressed on prior FGFRi therapy. Consistent with the FGFR2-selective mechanism, minimal off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) was seen. These encouraging data validate selective targeting of FGFR2 and suggest that RLY-4008 has potential to overcome resistance to FGFRi. Citation Format: Lipika Goyal, Mitesh Borad, Vivek Subbiah, Amit Mahipal, Suneel Kamath, Kabir Mody, Robin Katie Kelley, Richard Kim, Vaibhav Sahai, Anthony El-Khoueiry, Efrat Dotan, Oleg Schmidt-Kittler, Jinshan Shen, Kai Yu Jen, Alicia Deary, Wei Guo, Mahesh Padval, Cori Ann J. Sherwin, Charles Ferte, Beni Wolf, Alison M. Schram. First results of RLY-4008, a potent and highly selective FGFR2 inhibitor in a first-in-human study in patients with FGFR2-altered cholangiocarcinoma and multiple solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P02-02.

The NCCN Guidelines for Hepatobiliary Cancers focus on the screening, diagnosis, staging, treatment, and management of hepatocellular carcinoma (HCC), gallbladder cancer, and cancer of the bile ducts (intrahepatic and extrahepatic cholangiocarcinoma). Due to the multiple modalities that can be used to treat the disease and the complications that can arise from comorbid liver dysfunction, a multidisciplinary evaluation is essential for determining an optimal treatment strategy. A multidisciplinary team should include hepatologists, diagnostic radiologists, interventional radiologists, surgeons, medical oncologists, and pathologists with hepatobiliary cancer expertise. In addition to surgery, transplant, and intra-arterial therapies, there have been great advances in the systemic treatment of HCC. Until recently, sorafenib was the only systemic therapy option for patients with advanced HCC. In 2020, the combination of atezolizumab and bevacizumab became the first regimen to show superior survival to sorafenib, gaining it FDA approval as a new frontline standard regimen for unresectable or metastatic HCC. This article discusses the NCCN Guidelines recommendations for HCC.