Prognostic factors in RET dependent cancers treateded with RET inhibitors in early phase clinical trials.
Authors: Gordon Max , Roszik Jason , Cabanillas Maria E. , Hu Mimi I-Nan , Busaidy Naifa Lamki , Sherman Steven I. , Dadu Ramona , Grubbs Elizabeth Gardner , Elamin Yasir Y , Cascone Tina , Byers Lauren Averett , Blumenschein George R. , Fossella Frank V. , Naing Aung , Hong David S. , Heymach John , Meric-Bernstam Funda , Subbiah Vivek 
Published: June 2021

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Background: Activation of the RET proto-oncogene has been identified in multiple cancer types, for example, gene rearrangements in non-small cell lung cancer (NSCLC) and papillary thyroid cancer (PTC) and activating mutations in medullary thyroid cancer (MTC), amongst others. The recent FDA approval of two highly selective RET inhibitors, selpercatinib and pralsetinib has changed the treatment paradigm of RET-driven cancers, but the significance of historical prognostic factors is unknown. Herein, we analyzed the outcomes of patients with RET-altered cancers enrolled in phase I trials and assess the utility of prognostic scores. Methods: A retrospective analysis was performed of patients treated with selective RET inhibitors at the MD Anderson Cancer Center (MDACC). Baseline clinical factors and survival data were assessed. Overall and progression free survival (OS and PFS) were estimated using the Kaplan-Meier method and multivariable Cox models were constructed. For all a p-value of < 0.05 was consider significant. Results: Among 126 patients, median age was 58 years (range, 15-82), most with ECOG 0-1 (n = 124). RET-mutant MTC was most frequent (n = 81), followed by RET fusion-positive NSCLC (n = 30) and RET fusion positive thyroid cancer (n = 9). RET fusion partners were KIF5B (n = 17), CCD6 (n = 12) and NCOA4 (n = 7). RET M918T mutation was the most frequent (n = 50, 63%). Most patients were treated in the relapsed/refractory (R/R) setting (n = 85) and received a median of 1 prior line of therapy (range, 0-11). Median follow up was 20 months (range, 1-43). The estimated median PFS and OS were 24 and 35 months, respectively. Overall objective response rate was 64% (81/126), 2 complete response, 79 partial response, 32 had stable disease (25%) and 13 had progressive disease (PD). The following were associated with shorter PFS and OS: age ≥50 years (p < 0.05), albumin < 4 g/dL (p < 0.01), brain metastases (p < 0.0001), hemoglobin < 12 g/dL ( < 0.05), LDH > normal (p < 0.05), WBC ≥8 (p < 0.01), PD (p < 0.0001) and NSCLC (p < 0.01). The M918T mutation and ECOG > 0 were associated with shorter OS but not PFS (p < 0.05). > 3 metastatic sites and R/R disease were associated with inferior PFS (p = 0.04 and p = 0.01, respectively) but not OS. The Royal Marsden Hospital (RMH) and MDACC prognostic scores were significantly associated with PFS and OS (p < 0.01). In multivariable models including all variables significantly associated with PFS and OS (excluding LDH as this was only tested in 58 patients) albumin < 4 (HR 6.10, p = 0.013), brain metastases (HR 4.90, p = 0.027) and WBC ≥8 (HR 4.67, p = 0.031) were associated with inferior OS. NSCLC was significantly associated with inferior PFS (HR 5.45, p = 0.02). Conclusions: The RMH and MDACC prognostic scores predict OS in RET-aberrant cancers treated on early phase trials. Low albumin, WBC > 8 and brain metastases are significantly associated with inferior survival.