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Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRASG12C inhibition.

Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The median progression-free survival was 4.2 months, the median overall survival was 9.6 months, and the overall response rate was 17.5%. TP53, ERBB2, PI3KCA, FGFR3, and ARID1A alterations were detected in 66%, 29%, 27%, 24%, and 22% of all patients, respectively. Alterations in FGFR3 were almost mutually exclusive of TP53. More than half (64%) of patients with an FGFR alt received an FGFR inhibitor, 67% of which achieved disease control. Among patients with urothelial carcinoma histology, those harboring a TP53 alteration had a shorter median progression-free survival (PFS) compared with those whose tumors carry wild-type TP53. The reverse relationship was observed in patients harboring an FGFR alteration. Implications: Patients with platinum-refractory mBC derive clinical benefit from participating in early-phase clinical trials and their survival outcomes correlate with the genetic profile of the tumor. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/3/395/F1.large.jpg.

Purpose of review Bladder cancer is the 10th most common cancer in the world and the 6th most common cancer among men. In the past few years, several new agents have been approved for the treatment of urothelial tumors. In this paper, we review the evolving treatment landscape of advanced urothelial carcinoma (UC). Recent findings Since 2016, the Food and Drug Administration (FDA) has approved five immunotherapies targeting programmed cell death 1/programmed cell death 1 legend, an antinectin-4 antibody drug conjugate (ADC), and a fibroblast growth factor receptor (FGFR) inhibitor for the treatment of patients with advanced UC. Moreover, there are multiple targeted agents, immune checkpoint inhibitors (ICI), ADCs, and their combinations currently being tested in clinical studies with the goal of obtaining FDA approval. Summary Precision oncology efforts continue to advance our understanding of the UC biology and transform the existing treatment paradigms. An enlarging arsenal of treatment options promises further personalization of UC therapy.

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

Background: Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions have been recognized as potent drivers of oncogenesis in multiple malignancies. Recently, highly potent and selective RET inhibitors, selpercatinib and pralsetinib have been FDA approved for RET fusion+ NSCLC and selpercatinib for RET+ thyroid cancers. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Patients and methods: 96,324 samples from 89,754 patients available from AACR Project Genie database version 8 were analyzed for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types accessed July 21, 2020. The races of the samples within the cohort were 69,962 (72.6%) white, 5,388 (5.6%) Black, 4,909 (5.1%) Asian, 163 (0.17%) Native American, 48 (0.05%) Pacific Islander, and 15,854 (16.5%) were unknown. Results: There were 56,382 (58.5%) samples from primary tumors, 24,204 (25.1%) samples from unspecified metastasis sites, 4,798 (5.0%) from distant organ metastasis, 1,379 (1.4%) from lymph node metastasis, 1,279 (1.3%) from local recurrence, and 8,282 (8.6%) unknown. In 96,324 tumor samples there were 2,706 (2.81%) RET alterations. This included 223 (0.23%) fusions, 1,689 RET mutations found (1.75%) in 21 tumor histologies, and 794 (0.82%) RET amplifications identified; where the most abundant tissues harboring RET fusions were NSCLC (n = 121), papillary thyroid cancer (n = 53), breast cancer (n = 8) and colorectal cancer (n = 7) and the most abundant tissues harboring RET missense mutations were NSCLC (n = 355), colorectal cancer (n = 292), melanoma (n = 236), and thyroid cancer (n = 127). NSCLC samples with RET fusions had significantly co-altered KRAS, SETD2, PVRL4, EZH1, and RRAGC. Conclusions: RET fusions represent extremely rate events in multiple cancers. RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted because RET is highly targetable with therapeutics. Citation Format: Jacob J. Adashek, Alexander Andreev-Drakhlin, Jason Roszik, Aakash P. Desai, Vivek Subbiah. The landscape of 2,706 RET alterations from 89,754 adult patients with cancer: Clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1221.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.

487 Background: Tumors deficient in DNA mismatch repair (dMMR) exhibit a microsatellite unstable phenotype characterized by high tumor mutational burden and an immunogenic tumor microenvironment. Despite the histology-agnostic approval of pembrolizumab for advanced dMMR/MSI cancers, responsiveness of dMMR/MSI upper tract urothelial cancers (UTUC) to immune checkpoint (IC) blockade remains largely unknown. Methods: Consecutive records of patients (pts) from a single institution with locally advanced unresectable or metastatic dMMR/MSI UTUC who received IC therapy were analyzed. The primary endpoint was assessment of objective response rate (ORR) using RECIST v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier technique. dMMR/MSI status was evaluated by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR). Results: Ten pts were identified with locally advanced unresectable (N = 3) or metastatic (N = 7) dMMR/MSI UTUC who received therapy with IC blockade (pembrolizumab = 7, nivolumab = 2, atezolizumab = 1). Median age was 65.5 (range = 46 – 90). Six pts were male. Seven pts had germline dMMR. MSI was detected by PCR in three pts and dMMR by IHC in seven pts (PMS2/MLH1 loss = 4, MSH2 loss = 1, MLH1 loss = 1, MSH6 loss = 1). Five pts received systemic chemotherapy (2 cisplatin based, 1 carboplatin based, 2 other) prior to IC therapy with two pts (40%) achieving partial response (PR). At a median follow-up of 15.5 months (range: 2 – 43 months), all pts were alive, and none experienced disease progression. PFS and OS at 15.5 months were 100%. The observed ORR was 90% (CI, 55.5%, 99.8%), including 8 pts who achieved complete remission (CR). The median time to best response was 4 months (range: 2 – 8 months). Toxicity leading to treatment discontinuation: 1 (grade 3) pancytopenia, 1 (grade 2) pneumonitis, 1 (grade 2) SICCA-like symptoms. Conclusions: Immunotherapy with IC inhibitors demonstrates excellent clinical activity in advanced dMMR/MSI UTUC. Further studies integrating these agents earlier in the disease course are warranted in this rare but important subgroup. Given the extremely high complete response rate in this population consideration of preference to IC therapy as initial therapy should be entertained if these findings are validated.

Purpose The receptor tyrosine kinase rearranged during transfection (RET) can be oncogenically activated by gene fusions or point mutations. Multikinase inhibitors such as cabozantinib, lenvatinib and vandetanib have demonstrated activity in RET-dependent malignancies, and selective RET inhibitors (Selpercatinib and Pralsetinib) are in clinical trials. However, the responsiveness of RET-dependent malignancies to immune checkpoint inhibitors (ICIs) is unknown. We compared the time to treatment discontinuation (TTD) for ICI versus non-ICI therapy in patients with malignancies harbouring activating RET mutations or fusions (RET+). Methods A retrospective review of all RET+ patients who were referred to the phase I clinical trials programme at the University of Texas MD Anderson Cancer Center was conducted. TTD was estimated using Kaplan-Meier analysis. Multivariate analysis using the Cox proportional hazard model was performed to identify independent risk factors of treatment discontinuation. Results Of 70 patients who received systemic therapy for RET+ malignancies, 20 (28.6%) received ICI and 50 (71.4%) received non-ICI therapy. Non-ICI therapy was associated with decreased risk for treatment discontinuation compared with ICI in the overall population (HR=0.31; 95% CI 0.16–0.62; p=0.000834) and in patients with RET point mutations (HR=0.13; 95% CI 0.04–0.45; p=0.00134). In patients with RET fusions, non-ICI therapy was associated with a non-statistically significant decreased risk of treatment discontinuation (HR=0.59; 95% CI 0.25–1.4; p=0.24). ICI therapy and a diagnosis other than medullary thyroid cancer (MTC) were independent risk factors for treatment discontinuation. Conclusion Our study supports the prioritisation of non-ICI over ICI therapy in patients with RET+ tumours.

3106 Background: Activating receptor-tyrosine kinase rearranged during transfection ( RET) mutations and fusions have been recognized as potent drivers of oncogenesis. Recent identification of highly potent and selective RET inhibitors holds great promise in the management of RET-dependent tumors. Here we present a comprehensive analysis of RET alterations in pan-cancer adult malignancies. Methods: We analyzed 59,347 samples from 56,970 patients available from AACR Project GENIE (Cancer Discov. 2017) database for the prevalence of RET fusions, mutations, and copy number alterations in diverse cancer types. Results: A total of 1414 RET alterations were detected, including 91 fusions (6.4%), 1166 missense mutations (82.5%), 136 truncating mutations (9.6%), and 21 in-frame mutations (1.5%). RET fusions were observed in 0.15% of tumor samples and were most commonly identified in non-small cell lung cancer, thyroid cancer, colorectal cancer, prostate cancer, and gastric cancer (62.6%, 18.6%, 5.5%, 4.4%, 3.3% of identified RET fusions, respectively). RET fusions were significantly co-altered with MAPK3/ERK1 (p=0.045), SETD2 (p=1.36E-07 ), and EIF4E (p=0.045), while there was a negative association between RET fusions and EGFR (p=0.009634) , TP53 (p=0.02267), and KRAS (p=2.53E-05) alterations. Most common RET gene upstream partners were KIF5B, CCDC6, and NCOA4 (42.9%, 24.2%, 7.7% of identified RET fusions, respectively). RET missense mutations were found in 2.0% of tumor samples; 136 (11.7%) of identified missense mutations, including 8 RET gatekeeper V804M/L mutations, were characterized as likely oncogenic, 12 (1.0%) as likely benign, and 1018 (87.3%) as variants of unknown significance using OncoKB database. RET amplifications occurred in 1.5% of tested samples. Conclusions: While RET fusions represent extremely rare events in multiple cancers, RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations. Further functional characterization of RET variants is warranted. MAPK pathway co-alterations in patents with RET fusions may present a strategy for future therapeutic combinations.