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Purpose: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi., Patients and Methods: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed., Results: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit., Conclusions: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators., Patients and Methods: A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR)., Results: A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports., Conclusions: Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. See related commentary by Jangra and Dhani, p. 4521., (©2023 The Authors; Published by the American Association for Cancer Research.)

Importance: Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti-programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor., Objective: To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors., Design, Setting, and Participants: The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability-high (MSI-H) or polymerase epsilon (POLE)-altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months., Interventions: Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal., Main Outcomes and Measures: The primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1., Results: The efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified., Conclusions and Relevance: In this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need., Trial Registration: ClinicalTrials.gov Identifier: NCT02715284.

What Is This Summary About?: Dostarlimab, also known by the brand name JEMPERLI, is a medicine that can be used to treat certain types of endometrial cancer. GARNET is an ongoing phase 1 clinical study that is testing the safety and side effects of dostarlimab and the best way to administer it to patients. The results presented in this summary are from a time point in the middle of the study., What Were the Results?: The results from the GARNET study published in 2022 showed how well dostarlimab worked for people participating in the study. Dostarlimab was found to reduce the size of tumors in patients with certain types of endometrial cancer. The patients treated with dostarlimab had side effects that could be managed and few severe side effects., What Do the Results Mean?: The results of the GARNET study led to dostarlimab being approved to treat patients with certain types of endometrial cancer. For patients with advanced-stage endometrial cancer, or endometrial cancer that has come back after chemotherapy (recurrent), there are few treatment options. The results suggest that dostarlimab may provide long-term benefits for these patients.

Ovarian immature teratoma is a rare subtype of germ cell tumour that can be pure or associated with non-teratomatous germ cell tumour elements and is graded based on extent of the immature neuroectodermal component. Immature teratoma (IT) can also be associated with somatic differentiation in the form of sarcoma, carcinoma, or extensive immature neuroectodermal elements and may produce low levels of serum alpha-fetoprotein. Variable interpretation of these issues underlies diagnostic and management dilemmas, resulting in substantial practice differences between paediatric and adult women with IT. The Malignant Germ Cell International Consortium (MaGIC) convened oncologists, surgeons, and pathologists to address the following crucial clinicopathologic issues related to IT: (1) grading of IT, (2) definition and significance of 'microscopic' yolk sac tumour, (3) transformation to a somatic malignancy, and (4) interpretation of serum tumour biomarkers. This review highlights the discussion, conclusions, and suggested next steps from this clinicopathologic conference., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab., Methods: GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review., Results: Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab., Conclusion: Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile., Trial Registration Number: NCT02715284., Competing Interests: Competing interests: AO reports consulting fees from AstraZeneca, Bristol Meyers Squibb, Deciphera Pharmaceutical, Genmab, GlaxoSmithKline, ImmunoGen, Mersana Therapeutics, SUTRA, and Roche; institutional grants from Abbie Deutschland, Ability Pharmaceuticals, Advaxis Inc, Aeterna Zentaris, Amgen SA, Aprea Therapeutics AB, Clovis Oncology Inc, Eisai Ltd, F. Hoffmann-La Roche Ltd, GlaxoSmithKline, ImmunoGen Inc, and Merck Sharp & Dohme de Espana SA, Millennium Pharmaceuticals Inc, PharmaMar, and Regeneron Pharmaceuticals, and travel support from AstraZeneca, Clovis Oncology, PharmaMar, and Roche. LG reports institutional grants from AstraZeneca, Pfizer, and Merck Sharp & Dohme, Karyopharm, Tesaro, IMV, Alkermes, Clovis, ImmunoGen Inc, Roche, Mersana, Esperas, Novocure GmbH, OncoQuest Pharmaceuticals; consulting fees from Merck; honoraria from AstraZeneca, GlaxoSmithKline, Eisai, Eisai-Merck, and Alkermes. AVT reports institutional grants from AstraZeneca and personal fees from AstraZeneca and Eisai. JB reports honoraria from Olympus; consulting or advisory role at Caris, GlaxoSmithKline, Clovis, AstraZeneca, and Genentech; and speakers’ bureau at Clovis. CM reports institutional grants from GlaxoSmithKline. JP has nothing to disclose. RS reports institutional grants from AstraZeneca and Eisai; personal fees from AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, and Roche; and nonfinancial support from Amgen, AstraZeneca, Pfizer, and Roche. DMO'M reports personal fees from Agenus, Array Biopharma, Eisai, GlaxoSmithKline, and ImmunoGen; consultant/advisory board for Abbvie, Ambry, Amgen, Clovis, EMD Serono, Ergomed, Janssen/J&J, Myriad Genetics, Novacure, Regeneron, Tarveda, and VentiRx; steering committee for Genentech/Roche and Merck; institutional funding from Ajinomoto Inc, Bristol Myers Squibb, Cerulean Pharma, GOG Foundation, INC Research Inc, Inventiv Health Clinical, Iovance Biotherapeutics Inc, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA International, Serono Inc, Stemcentrx Inc, Tracon Pharmaceuticals, and Yale University. VS has nothing to disclose. VB reports consulting or advisory roles at Guidepoint Global and OncoArt; speakers’ bureau fees from Solti; travel support from START; honoraria from Loxo and IDEAYA Biosciences; and institutional grants from Abbvie, Adaptimmune, Alkermes, Amgen, Array BioPharma, AstraZeneca, Bayer, BioNTech AG, Boehringer Ingelheim, Boston Biomedical, Bristol Myers Squibb, CytomX Therapeutics, Genmab, GlaxoSmithKline, Incyte, Janssen Oncology, Kura Oncology, Lilly, Loxo, Menarini, Merck, Merus, Novartis, Pfizer, Pumo Biotechnology, Roche/Genentech, Sanofi, Seattle Genetics, Synthon, and Zenith Epigenetics. LD reports personal fees from Advance Medical, ASCO, AstraZeneca, British Journal of OB/GYN, ClearView Health Care, Cue Biopharma, Elsevier, Genentech/Roche, Innovio, JB Learning, Merck, MorphoTek, National Cancer Institute, Parexel, State of California, and UpToDate; and institutional grants from Abbvie, Advaxis, Aduro BioTech, Cerulean/NextGen, Eisai, Genentech/Roche, GlaxoSmithKline, Inovio, LEAP Therapeutics, Ludwig, Lycera, Morab, Morphotek, Merck, Novartis, Pfizer, and Syndax. SG reports consulting or advisory role from Seattle Genetics; speakers’ bureau fees from GlaxoSmithKline; and institutional research funding from Abbvie, Advaxis, Bristol Myers Squibb, Clovis, Genentech, GlaxoSmithKline, Merck, Roche, Seattle Genetics, and Takeda. PG has nothing to disclose. RK reports personal fees from GlaxoSmithKline. CL reports contracted research for GlaxoSmithKline and scientific advisory board fees from GlaxoSmithKline, Eisai, Clovis Oncology, Seattle Genetics, and AbbVie. WG is a former employee of GlaxoSmithKline. EI is a former employee of GlaxoSmithKline. SZ, XH, TD, and JV are employees of GlaxoSmithKline. BP reports institutional grants support from Tesaro/GSK, AstraZeneca, Merck, Genentech/Roche, Celsion, Mersana, Karyopharm, and Clovis Oncology; and advisory board fees from Tesaro/GSK, AstraZeneca, Merck, Eisai, Toray, Mersana, Elevar Therapeutics, Arquer Diagnostics, Sutro Biopharma, and Clovis Oncology., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Uterine serous carcinoma (USC) is a distinct histologic subtype of endometrial cancer, with molecular characteristics suggesting frequent cell-cycle dysregulation paired with a high level of oncogene-driven replication stress. Adavosertib is a potent and selective oral inhibitor of the WEE1 kinase, a key regulator of the G2/M and S phase cell-cycle checkpoints. Because cells with impaired cell-cycle regulation and high replication stress may be vulnerable to WEE1 inhibition, we conducted this study to assess the activity of adavosertib monotherapy in women with recurrent USC., Patients and Methods: This was a single-arm two-stage phase II study with coprimary end points of objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6). Women with recurrent USC were treated with adavosertib monotherapy at a starting dose of 300 mg orally once daily days 1 through 5 and 8 through 12 of a 21-day cycle until disease progression., Results: In 34 evaluable patients, 10 total responses (one confirmed complete response, eight confirmed partial responses, and one unconfirmed partial response) were observed with adavosertib monotherapy, for an ORR of 29.4% (95% CI, 15.1 to 47.5). Sixteen patients were progression-free at 6 months, for a PFS6 rate of 47.1% (95% CI, 29.8 to 64.9). Median PFS was 6.1 months, and median duration of response was 9.0 months. Frequent treatment-related adverse events (AEs) included diarrhea (76.5%), fatigue (64.7%), nausea (61.8%), and hematologic AEs. No clear correlation of clinical activity with specific molecular alterations was observed in an exploratory biomarker analysis., Conclusion: Adavosertib monotherapy demonstrated encouraging and durable evidence of activity in women with USC, and further investigation of this agent in this cancer and biomarkers of activity are indicated., Competing Interests: Joyce F. LiuConsulting or Advisory Role: Tesaro, Mersana, Clovis Oncology, Genentech/Roche, GlaxoSmithKline, Regeneron, AstraZenecaResearch Funding: Genentech/Roche, AstraZeneca, Boston Biomedical, Atara Biotherapeutics, Acetylon Pharmaceuticals, Bristol-Myers Squibb, Agenus, CytomX Therapeutics, Regeneron, Tesaro, Clovis Oncology, Surface Oncology, 2X Oncology, Vigeo Therapeutics, Aravive, Arch OncologyTravel, Accommodations, Expenses: AstraZeneca, Merck(OPTIONAL) Uncompensated Relationships: Merck Susana M. CamposHonoraria: AstraZeneca, EisaiConsulting or Advisory Role: GlaxoSmithKline, Eisai, AstraZeneca Carolyn KrasnerResearch Funding: Cerulean Pharma Susan SchumerStock and Other Ownership Interests: Johnson and Johnson Neil HorowitzPatents, Royalties, Other Intellectual Property: Up to Date Author Jennifer VenerisEmployment: Abbott Laboratories, Takeda, GlaxoSmithKlineStock and Other Ownership Interests: AbbvieHonoraria: Michiana Hematology Oncology Ursula A. MatulonisHonoraria: AdvaxisConsulting or Advisory Role: Merck, Novartis, NextCureResearch Funding: Merck, Novartis, Tesaro, Syndax, Immunogen. Mersana, Leap Therapeutics, Fujifilm, SQZ BiotechTravel, Accommodations, Expenses: AstraZeneca Panagiotis A. KonstantinopoulosConsulting or Advisory Role: Merck, Vertex, AstraZeneca, Pfizer/EMD Serono, Tesaro, Bayer, AlkermesResearch Funding: Pfizer, Lilly, Tesaro, Merck Serono, AstraZeneca, Merck, BayerNo other potential conflicts of interest were reported.

Here we present a transgender male adolescent with an androgen receptor-positive serous borderline ovarian tumour in the setting of testosterone treatment for medical gender transition. To our knowledge, this is the second report of borderline tumour in a transgender individual and the first in an adolescent, an age group in which borderline tumours are extremely rare. We discuss the specific considerations of treating ovarian tumours in the transgender male population, the incompletely understood role of androgens in the genesis of ovarian epithelial neoplasia, and an emphasis on assessing cancer risk in transgender patients based on patient anatomy.

Objective: Patients with advanced/recurrent epithelial ovarian and uterine cancers have limited treatment options beyond platinum chemotherapy. Both tumor types can express programmed death-ligand 1 (PD-L1), providing a potential therapeutic target for these patients. Here we present data from the ovarian and uterine cancer cohorts of the Phase I atezolizumab monotherapy study (PCD4989g)., Methods: This Phase I, multi-center, first-in-human, open-label, dose-escalation/expansion clinical trial investigated single-agent atezolizumab in cohorts of patients with recurrent epithelial ovarian or uterine cancer. The primary objective was to evaluate the safety and tolerability of single-agent atezolizumab. Anti-tumor activity and preliminary assessment of potential biomarkers were evaluated as secondary and exploratory objectives, respectively., Results: The ovarian and uterine cancer cohorts enrolled 12 and 15 patients, respectively (10 [83%] and 5 [33%], respectively, had PD-L1 ≥ 5% on tumor-infiltrating immune cells). Atezolizumab was generally well tolerated with no new safety signals identified. The safety profiles in both cohorts were consistent with the known profile of atezolizumab monotherapy. Treatment-related adverse events (AEs) were mostly Grade ≤ 2, with no treatment-related Grade ≥ 4 AEs reported. Preliminary anti-tumor activity, with long durations of response, was observed in 2 patients from each cohort (ovarian cancer, 8.1 and 30.6+ months; uterine cancer, 7.3 and 16.6+ months). High microsatellite instability and tumor mutational burden were noted in the responders from the uterine cancer cohort., Conclusions: Atezolizumab monotherapy was well tolerated in patients with epithelial ovarian or uterine cancer and may have clinical activity warranting further investigation., Trial Registration: ClinicalTrials.gov identifier: NCT01375842., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Metastatic dissemination in prostate cancer is often early, but not all cancer cells form clinical metastases. Map kinase kinase 4 (MKK4) suppresses metastasis in a preclinical prostate cancer model. We hypothesize that MKK4 will specifically inhibit metastatic colonization through impaired proliferation. Three highly metastatic rat prostate cancer cell lines (AT6.1, Mat-Lu and AT3.1) were employed. Stably over-expressing HA-MKK4 or vector control lines were injected into immunocompromised mice. These experiments validated that HA-MKK4 specifically affects metastatic colonization and increases survival. Median survival (days) with HA-MKK4 vs. vector was 42 vs. 28 (p < 0.0001) for AT6.1, 25 vs. 19 (p < 0.0001) for Mat-Lu and 27 vs. 20 (p < 0.0001) for AT3.1. HA-MKK4 suppresses colonization within 14 days post dissemination, after which exponential proliferation resumes. Although overt metastases retain HA-MKK4, it is inactive within these lesions. Nonetheless, metastasis-derived cell lines were shown to retain functional HA-MKK4 and like their parental HA-MKK4 line are suppressed for experimental metastasis formation in vivo. Disseminated AT6.1-HA-MKK4 cells were analyzed and were found to have an alteration in cell cycle. Specifically, there was an accumulation of cells in G1-phase (p = 0.024) and decrease in S-phase (p = 0.037) compared with vector. In multiple prostate cancer lines, HA-MKK4 suppresses an early step in metastatic colonization. These data support a model in which MKK4 activation at the metastatic site causes a cell-cycle arrest, which is eventually overcome despite presence of functional HA-MKK4. Further studies will specifically interrogate the regulation of MKK4 activation within the metastatic microenvironment and the down-stream molecular events critical for metastasis suppression., (Copyright © 2011 UICC.)