Turner, Christopher D.

467 Background: Recent tumor-agnostic drug approvals have resulted in a paradigm shift in cancer treatment away from organ/histology specific indications to biomarker-guided tumor-agnostic approaches. Pralsetinib is a potent and selective RET inhibitor, which has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with metastatic RET fusion–positive non-small cell lung cancer (NSCLC) and is under New Drug Application review for RET mutant thyroid cancers by the FDA. RET fusions occur in up to approximately 7‒8% of patients with gastrointestinal malignancies, including pancreatic, liver, and colorectal cancers. There are currently no approved selective RET inhibitors for patients with RET fusion–positive solid tumors other than NSCLC and thyroid cancer. Here, we present data on the clinical activity of pralsetinib in patients with RET fusion–positive solid tumor types other than NSCLC enrolled in the Phase I/II ARROW study (NCT03037385). Methods: ARROW consists of a phase I dose escalation (30–600 mg once [QD] or twice daily) followed by a phase II expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives are overall response rate (ORR), per RECICT v1.1 and safety. Results: A total of 13 patients with RET fusion–positive thyroid cancer (12 papillary, 1 poorly differentiated; enrollment cutoff July 11, 2019) and 14 patients with RET fusion–positive solid tumors other than NSCLC and thyroid (3 pancreatic, 3 colon, 2 cholangiocarcinoma, 6 other; enrollment cutoff November 19, 2019) were enrolled in ARROW and received pralsetinib. At the February 13, 2020, data cutoff, the ORR (blinded central review) in response-evaluable patients with RET fusion–positive thyroid cancer was 91% (10/11; 95% CI: 59‒100) and disease control rate was 100% (95% CI: 72‒100). Treatment was ongoing in 7 of 11 patients. In RET fusion–positive solid tumors other than NSCLC and thyroid, ORR (investigator’s assessment) was 50% (6/12; 95% CI: 21‒79) and responses were observed in all patients with pancreatic cancer (3/3) and cholangiocarcinoma (2/2). Treatment was ongoing in 6 of 12 patients, including 2 of 3 patients with pancreatic cancer and 1 of 2 patients with cholangiocarcinoma. Responses were observed across multiple fusion genotypes. In the 27 patients with RET fusion–positive tumors other than NSCLC, most frequent treatment-related adverse events (TRAEs) were grade 1–2, and included anemia (33%), increased aspartate aminotransferase (33%), decreased white blood cell count (33%), hypertension (30%), increased alanine aminotransferase (26%), hyperphosphatemia (19%), and neutropenia (19%). No patients discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing. Clinical trial information: NCT03037385.

Glembatumumab vedotin (CDX-011, GV) is a fully human Immunoglobulin G2 monoclonal antibody directed against glycoprotein NMB coupled via a peptide linker to monomethyl auristatin E (MMAE), a potent cytotoxic microtubule inhibitor. This phase II study evaluated the overall response rate and safety of GV, glycoprotein NMB (GPNMB) expression, and survival in patients with metastatic uveal melanoma. Eligible patients with metastatic uveal melanoma who had not previously been treated with chemotherapy received GV 1.9 mg/kg every three weeks. The primary endpoint was the objective response rate (ORR). Secondary endpoints included GPNMB expression, progression-free survival (PFS), overall survival (OS), and toxicity analysis. GPNMB expression was assessed pre- and post-treatment via immunohistochemistry for patients with available tumor tissue. Out of 35 patients who received treatment, two patients had confirmed partial responses (PRs; 6%), and 18 patients had a stable disease (SD; 51%) as the best objective response. 38% of the patients had stable disease >100 days. The grade 3 or 4 toxicities that occurred in two or more patients were neutropenia, rash, hyponatremia, and vomiting. The median progression-free survival was 3.1 months (95% CI: 1.5–5.6), and the median overall survival was 11.9 months (95% CI 9.0–16.9) in the evaluable study population. GV is well-tolerated in metastatic uveal melanoma. The disease control rate was 57% despite a low objective response rate. Exploratory immune correlation studies are underway to provide insight into target saturation, combination strategies, and antigen release.

109 Background: RET gene fusions are targetable oncogenic drivers in multiple tumor types, including up to 20% of papillary thyroid cancers (PTC). Pralsetinib is an investigational, highly potent, selective inhibitor of oncogenic RET alterations. In the registration-enabling Phase 1/2 ARROW study (NCT03037385), pralsetinib demonstrated an overall response rate (ORR; response-evaluable patients [REP], central review) of 73% (19/26) in treatment-naïve patients and 61% (49/80; 2 pending confirmation) in platinum-exposed patients with RET fusion+ non-small cell lung cancer (NSCLC) and was well tolerated (data cut-off November 18, 2019). We provide an update on the clinical activity of pralsetinib in other RET fusion+ solid tumor types. Methods: ARROW consists of a phase 1 dose escalation (30–600 mg once [QD] or twice daily) followed by a phase 2 expansion (400 mg QD) in patients with advanced RET-altered solid tumors. Primary objectives were ORR and safety. Results: As of November 18, 2019, 29 patients with metastatic solid tumor types other than NSCLC (16 PTC, 1 undifferentiated thyroid, 3 pancreatic, 3 colon, 6 other) bearing a RET fusion have received pralsetinib. Efficacy data are presented for REP enrolled by July 11, 2019. In patients with thyroid cancer that is RET fusion+, ORR (investigator assessment) was 75% (9/12; all confirmed). Median (range) duration of response (DOR) was 14.5 (3.7+, 16.8) months (mo), with 67% of responding patients continuing treatment. Two patients with stable disease were continuing treatment at 11.5+ and 19.3+ mo. In other RET fusion+ cancers, ORR was 60% (3/5; all confirmed) with partial responses in 2/2 patients with pancreatic cancer (DOR 5.5, 7.4+ mo) and 1 patient with intrahepatic bile duct carcinoma (DOR 7.5 mo). Two patients with colon cancer had stable disease for 7.3 and 9.3 mo. Responses were observed across multiple fusion genotypes. In the entire safety population (all patients treated with 400 mg QD pralsetinib, regardless of diagnosis; n = 354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). Only 4% of patients in the safety population discontinued due to TRAEs. Conclusions: Pralsetinib demonstrated broad and durable antitumor activity across multiple advanced solid tumor types, regardless of RET fusion genotype, and was well tolerated. The study is ongoing and still enrolling patients in this cohort. Clinical trial information: NCT03037385.