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Patients with advanced and/or recurrent gynecologic cancers derive limited benefit from currently available cytotoxic and targeted therapies. Successes of immunotherapy in other difficult-to-treat malignancies such as metastatic melanoma and advanced lung cancer have led to intense interest in clinical testing of these treatments in patients with gynecologic cancers. Currently, in the realm of gynecologic oncology, the FDA-approved use of immune checkpoint inhibitors is limited to microsatellite instability-high cancers, cancers with high tumor mutational burden, and PD-L1-positive cervical cancer. However, there has been an exponential growth of clinical trials testing immunotherapy approaches both alone and in combination with chemotherapy and/or targeted agents in patients with gynecologic cancers. This chapter will review some of the major reported and ongoing immunotherapy clinical trials in patients with endometrial, cervical, and epithelial ovarian cancer., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Immunotherapy has become a powerful treatment option for several solid tumor types. The presence of tumor-infiltrating lymphocytes (TIL) is correlated with better prognosis in ovarian cancer, pointing at the possibility to benefit from harnessing their anti-tumor activity. This preclinical study explores the feasibility of adoptive cell therapy (ACT) with TIL using an improved culture method., Methods: TIL from high-grade serous ovarian cancer were cultured using a combination of IL-2 with agonistic antibodies targeting 4-1BB and CD3. The cells were phenotyped using flow cytometry in the fresh tissue and after expansion. Tumor reactivity was assessed against HLA-matched ovarian cancer cell lines via IFN-γ ELISPOT., Results: Ovarian cancer is highly infiltrated with CD8 + TIL that are preferentially and robustly expanded with the addition of the agonistic antibodies. With a 95% success rate, the TIL are grown to ≥ 100 × 10 6 cells in 2-3 weeks without over differentiation. In addition, the CD8 + TIL grown with this method showed HLA-restricted tumor recognition., Conclusions: These results indicate the viability of TIL ACT for refractory ovarian cancer by allowing for the large expansion of anti-tumor TIL in a short time and consistent manner.

Although there has been significant progress in prevention and treatment of cervical cancer, this malignancy is still a leading cause of cancer death for women. Anti-angiogenesis and immunotherapy approaches have been providing survival benefits, however, response rates and durability of response need to be improved. There is a clear need for combination therapies that increase effectiveness of these agents and further improve patient outcome. Previous studies have largely focused on gene expression and molecular pathways in untreated cervix cancer. The goal of this study was to evaluate cancer-specific molecular pathways and their correlation with tumor immune profile in recurrent cervical cancer. Tumor and adjacent normal tissues were used to identify potential combination therapy targets. We found that DNA damage repair pathway genes were significantly overexpressed in the tumor. Based on our results and other recent investigations, we suggest that combination immune checkpoint and PARP inhibitor therapy is a high priority consideration for patients with recurrent, previously treated cervical cancer. We also show that multiple epithelial-mesenchymal transition-related genes, including MAP2K4, ID2, JAK1, FGF2, PIK3R1, AKT3, FGF13, and STAT3 may be potential targets. Interestingly, high-throughput analysis of Cancer Genome Atlas data identified distinct targets, including Fatty acid synthase FASN and Matrix Metallopeptidase 1 MMP1 as novel, promising combination therapy partners.

Opinion Statement: Immune-targeted therapies have demonstrated durable responses in many tumor types with limited treatment options and poor overall prognosis. This has led to enthusiasm for expanding such therapies to other tumor types including gynecologic malignancies. The use of immunotherapy in gynecologic malignancies is in the early stages and is an active area of ongoing clinical research. Both cancer vaccines and immune checkpoint inhibitor therapy continue to be extensively studied in gynecologic malignancies. Immune checkpoint inhibitors, in particular, hold promising potential in specific subsets of endometrial cancer that express microsatellite instability. The key to successful treatment with immunotherapy involves identification of the subgroup of patients that will derive benefit. The number of ongoing trials in cervical, ovarian, and endometrial cancer will help to recognize these patients and make treatment more directed. Additionally, a number of studies are combining immunotherapy with standard treatment options and will help to determine combinations that will enhance responses to standard therapy. Overall, there is much enthusiasm for immunotherapy approaches in gynecologic malignancies. However, the emerging data shows that with the exception of microsatellite unstable tumors, the use of single-agent immune checkpoint inhibitors is associated with response rates of 10-15%. More effective and likely combinatorial approaches are needed and will be informed by the findings of ongoing trials.

During the past decade significant progress in the understanding of stimulatory and inhibitory signaling pathways in immune cells has reinvigorated the field of immuno-oncology. In this review we outline the current immunotherapy based approaches for the treatment of gynecological cancers, and focus on the emerging clinical data on immune checkpoint inhibitors, adoptive cell therapies, and vaccines. It is anticipated that in the coming years biomarker-guided clinical trials, will provide for a better understanding of the mechanisms of response and resistance to immunotherapy, and guide combination treatment strategies that will extend the benefit from immunotherapy to patients with gynecologic cancers., Competing Interests: The authors report no relevant conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The metalloproteinase SAS1B [ovastacin, ASTL, astacin-like] was immunolocalized on the oolemma of ovulated human oocytes and in normal ovaries within the pool of growing oocytes where SAS1B protein was restricted to follicular stages spanning the primary-secondary follicle transition through ovulation. Gene-specific PCR and immunohistochemical studies revealed ASTL messages and SAS1B protein in both endometrioid [74%] and malignant mixed Mullerian tumors (MMMT) [87%] of the uterus. A MMMT-derived cell line, SNU539, expressed cell surface SAS1B that, after binding polyclonal antibodies, internalized into EEA1/LAMP1-positive early and late endosomes. Treatment of SNU539 cells with anti-SAS1B polyclonal antibodies caused growth arrest in the presence of active complement. A saporin-immunotoxin directed to SAS1B induced growth arrest and cell death. The oocyte restricted expression pattern of SAS1B among adult organs, cell-surface accessibility, internalization into the endocytic pathway, and tumor cell growth arrest induced by antibody-toxin conjugates suggest therapeutic approaches that would selectively target tumors while limiting adverse drug effects in healthy cells. The SAS1B metalloproteinase is proposed as a prototype cancer-oocyte tumor surface neoantigen for development of targeted immunotherapeutics with limited on-target/off tumor effects predicted to be restricted to the population of growing oocytes.

Background: Immune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies. Methods: The primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival. Results: Forty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed. Conclusions: The findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted. In a phase 1/2 trial of heavily pretreated patients who had recurrent gynecologic cancers, avelumab in combination with a 4‐1BB agonist, an OX40 agonist, and/or radiation was safe and had a similar rate of immune‐related adverse events compared with single‐agent immune checkpoint blockade. The combination of multiple immune‐modulating agents, however, did not result in increased efficacy. [ABSTRACT FROM AUTHOR]

Background Human papillomavirus (HPV) types 16/18 drive oncogenesis for most patients with cervical, anal, and penile cancers. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 HPV-16/18 viral oncogenes and IL-12 adjuvant, is safe and provokes an immune response against E6/E7. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for patients with HPV-associated cancers. Methods Patients with recurrent/metastatic, treatment-refractory HPV-16/18 cervical cancer, or rare HPV-associated (anal and penile) cancers were eligible. Prior immune checkpoint inhibition was not permitted. Patients received MEDI0457 7 mg intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks. The primary endpoint was overall response (RECIST 1.1). In this Simon two-stage phase 2 trial (Ho: p  < 0.15; Ha: p  ≥ 0.35), ≥2 responses were needed in both cervical and non-cervical cohorts during the first stage for the trial to proceed to stage 2 with an additional 25 patients (34 total) enrolled. Results Twenty-one patients (12 cervical, 7 anal, and 2 penile) were evaluable for toxicity and 19 for response Overall response rate was 21% (95% CI, 6%-46%) among evaluable patients. Disease control rate was 37% (95% CI, 16%-62%). Median duration of response among responders was 21.8 months (95% CI, 9.7%-not estimable). Median progression-free survival was 4.6 months (95% CI, 2.8%-7.2%). Median overall survival was 17.7 months (95% CI, 7.6%-not estimable). Grades 3-4 treatment-related adverse events occurred in 6 (23%) participants. Conclusions The combination of MEDI0457 and durvalumab demonstrated acceptable safety and tolerability in patients with advanced HPV-16/18 cancers. The low ORR among patients with cervical cancer led to study discontinuation despite a clinically meaningful disease control rate. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for patients with resectable MM. Method: Under an institutionally approved protocol, we identified adult MM patients with resectable disease who received neoadjuvant anti-PD1 +/- anti- CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade =3 toxicities. Results: We identified 36 patients. Median age was 62; 58% were female. Seventy-eight percent of patients received anti-PD1 + anti-CTLA4. Node positive disease or satellite lesions was present at the time of treatment initiation in 47% of patients. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of patients did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2 months with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for patients with objective response and for patients with pathologic response. OS was significantly higher for patients with pathologic response. Grade 3 toxicities were reported in 39% of patients. Conclusion: Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a crucial need to improve treatment regimens in patients with recurrent endometrial cancer. Although immunotherapy treatments have shown impressive benefit in microsatellite instability-high endometrial cancer, they have been less predictable in the majority of endometrial cancers, which are microsatellite stable. Our aim was to characterize clinical outcomes in patients with recurrent microsatellite stable endometrial cancer treated in early-phase immunotherapy clinical trials in order unravel treatment regimens that would improve response and survival. Our findings suggest that utilizing immunotherapy in combination with other non-immunotherapy agents resulted in greater duration of disease control and improved survival outcomes compared to immunotherapy only (monotherapy) or in combination with other immunotherapy agents. Future studies are needed to validate these findings. Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO plus non-IO therapy, one had a partial response but 50% had clinical benefit. Patients who received combination IO plus non-IO therapy had improved PFS compared to those who received monotherapy (HR 0.56, 95% CI 0.33–0.97; p = 0.037) or combination IO-only therapy (HR 0.36, 95% CI 0.15–0.90; p = 0.028) and had improved OS when compared to monotherapy after adjusting for prior lines of therapy (HR 0.50, 95% CI 0.27–0.95; p = 0.036). The potential beneficial clinical outcomes of combination IO plus non-IO therapy in MSS endometrial cancer should be validated in a larger study. [ABSTRACT FROM AUTHOR]

Abstract The success of targeted and immune therapies in other malignancies has led to an exponential increase in the number of active and pending clinical trials using these therapeutic approaches in patients with gynecologic cancers. These novel investigational agents are associated with unique and potentially life-threatening toxicities and many require special multidisciplinary logistical considerations. The objective of this review is to describe a practical approach for the safe implementation of targeted and immune therapies in academic gynecologic oncology practices based on our experience at M.D. Anderson Cancer Center. Highlights • This review provides a system-based practical approach for the safe implementation of targeted and immune therapies. • Creation of a multidisciplinary EDDIT team can provide shared experience and enhanced patient safety. • Education of providers, staff, trainees, and patients is a key function of the EDDIT team. • Immediate access to expert advice serves to avoid delays in recognition and management of adverse events. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. In addition to HPV antigens, neoantigens derived from somatic mutations may also generate an effective immune response and represent an additional and distinct immunotherapy strategy against this and other HPV-associated cancers. To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides in two large sequencing data sets and analyzed whether mutation and neoantigen load correlate with antigen presentation, infiltrating immune cell types, and a HPV-induced master regulator gene expression signature. We found that targetable neoantigens are detected in most tumors, and there are recurrent mutated peptides from known oncogenic driver genes (KRAS, MAPK1, PIK3CA, ERBB2, and ERBB3) that are predicted to be potentially immunogenic. Our studies show that HPV-induced master regulators are not only associated with HPV load but may also play crucial roles in relation to mutation and neoantigen load, and also the immune microenvironment of the tumor. A subset of these HPV-induced master regulators positively correlated with expression of immune-suppressor molecules such as PD-L1, TGFB1, and IL-10 suggesting that they may be involved in abrogating antitumor response induced by the presence of mutations and neoantigens. Based on these results, we predict that HPV master regulators identified in our study might be potentially effective targets in cervical cancer. [ABSTRACT FROM AUTHOR]

There is mounting evidence that the immune system plays an important role in the development and growth of gynecologic malignancies, and preliminary studies show activity of immune checkpoint inhibitors in ovarian, endometrial, and cervix cancer. In this review, we outline the completed trials of immune checkpoint blockade in the treatment of gynecologic malignancies. In addition, we review the ongoing trials in each disease site. The questions of which patients will benefit from immune checkpoint inhibitors and when immune checkpoint inhibitors should be incorporated into the treatment of gynecologic malignancies continue to be largely unanswered. As preclinical and clinical data emerge regarding predictive markers for response and resistance to immune checkpoint inhibitors, rational combination treatment strategies will help to further develop this emerging field in the treatment of gynecologic malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs in healthy adults but is also re-expressed in ovarian, colorectal and lung cancers. In this context, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody, currently in clinical trial. Preliminary data suggest that murlentamab anti-tumor activity involves immune response activation. Thus, in vitro experiments were performed to precisely characterize the murlentamab effect on the human immune system. We show that murlentamab treatment is associated with evidences of innate and adaptive immune cell activation in cancer patient samples. Moreover, we demonstrate that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells promotes a polarization switch of both naïve and tumor-associated macrophages towards an anti-tumor M1-like phenotype. Our work also supports that, through macrophage reeducation, murlentamab activates an anti-tumor adaptive immune response. Finally, the combination of murlentamab with pembrolizumab confirmed novel clinical perspectives of murlentamab association with checkpoint inhibitors and other immuno-modulators. AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and TAM-like macrophages to an M1-like phenotype characterized by a strong expression of co-stimulation markers, pro-inflammatory cytokines and chemokines, favoring T cell recruitment and activation. Moreover, we show that murlentamab treatment shifts CD4+ Th1/Th2 balance towards a Th1 response and activates CD8+ T cells. Altogether, these results suggest that murlentamab, through naïve macrophage orientation and TAM reprogrammation, stimulates the anti-tumor adaptive immune response. Those mechanisms might contribute to the sustained clinical benefit observed in advanced cancer patients treated with murlentamab. Finally, the enhanced murlentamab activity in combination with pembrolizumab opens new therapeutic perspectives. [ABSTRACT FROM AUTHOR]

Simple Summary: Knowledge of ovarian cancer molecular characteristics is increasingly crucial to individualizing and optimizing treatment strategies for this heterogeneous disease. Molecular features such as germline or somatic mutations, homologous recombination deficiency (HRD) status, microsatellite instability, and tumor mutational burden are associated with increased susceptibility to poly-ADP ribose polymerase inhibitors (PARPi) or immunotherapy. Our aim was to characterize these molecular features among ovarian cancer patients and determine their association with survival. Two different HRD score thresholds were evaluated: one currently used in clinics (≥42) and another proposed as a new threshold (≥33). An HRD score ≥33 was associated with improved overall survival in ovarian cancer. As HRD assays are increasingly used for treatment planning, future studies should evaluate an HRD score threshold of ≥33 compared to the currently used threshold of ≥42 for PARPi use. New therapies, such as poly-ADP ribose polymerase inhibitors (PARPi), and immunotherapy treatments have generated great interest in enhancing individualized molecular profiling of epithelial ovarian cancer (EOC) to improve management of the disease. In EOC patients, putative biomarkers for homologous recombination deficiency (HRD), microsatellite instability (MSI), and tumor mutational burden (TMB) were characterized and correlated with survival outcomes. A series of 300 consecutive EOC patients were enrolled. Patients underwent neoadjuvant chemotherapy (n = 172) or primary cytoreductive surgery (n = 128). Molecular profiling and survival analyses were restricted to the primary cytoreductive surgery cohort due to tissue availability. All patients underwent germline testing for HRD- and MSI-related gene mutations. When sufficient tissue was available, screening for somatic BRCA1/2 mutations, BRCA1 promoter methylation, HRD score (a measure of genomic instability), MSI, and TMB testing were performed. HRD score ≥33 was associated with improved overall survival on multivariable analysis. In the era of biomarker-driven clinical care, HRD score ≥33 may be a useful adjunctive prognostic tool and should be evaluated in future studies to predict PARPi benefits. [ABSTRACT FROM AUTHOR]

To determine the clinical predictors of response rate, progression-free survival (PFS), and overall survival (OS) to pembrolizumab in advanced or recurrent, mismatch repair deficient (MMRd) or Microsatellite Instability-High (MSI-H) endometrial adenocarcinomas. A retrospective, single institution study was conducted among women with recurrent or advanced MMRd or MSI-H endometrial adenocarcinomas treated with single-agent pembrolizumab at our institution from 2017 to 2021. Logistic regression was used for univariable and multivariable analyses. PFS and OS were estimated using the methods of Kaplan and Meier and modeled via Cox proportional hazards regression. Log-rank test was used for intergroup comparisons based on body mass index (BMI). Among the 44 patients included in the analysis, the median BMI was 32.9 (range 18.5–51.8). Median cycles of pembrolizumab given was 11.5 (range 2–37). Median follow-up was 33 months (range 5–61) with a response rate of 63.6% and stable disease rate of 75%. When stratified by obesity status (BMI ≥ 30), disease control rate was 59.8% in patients with a BMI < 30 and 85.2% in patients with a BMI ≥ 30 patients (p = 0.05). On multivariable analysis, obesity was associated with increased rate of disease control (OR 4.03, 95%CI 1.09, 28) while prior smoking was associated with decreased rate of disease control (OR 0.18, 95%CI 0.03, 0.85). PFS was significantly increased among patients with a BMI ≥ 30 (p = 0.03) but OS was similar (p = 0.5). In this retrospective study, obesity is associated with increased rates of disease control and improved PFS in patients treated with pembrolizumab for recurrent or advanced MMRd/MSI-H endometrial adenocarcinomas. • Obesity is a known risk factor for many cancers, yet is associated with improved treatment response in some tumor types. • Obesity is associated with improved disease control in patients with MMRd endometrial cancer when treated with pembrolizumab. • PFS was significantly increased among patients with a BMI ≥ 30 but overall survival was similar. [ABSTRACT FROM AUTHOR]

Gynecologic tract melanoma (GTM) is a rare malignancy with historically poor outcomes. The current study examines patterns of care and oncologic outcomes in a large single-institution cohort from the contemporary therapeutic era. Patterns of care and predictors of outcomes were evaluated for all GTM patients without metastatic disease at diagnosis who were treated at our institution between 2009 and 2020 with >6 months of follow-up. Of the 124 patients included, anatomic subsites were vulvar (n = 82, 66%), vaginal (n = 34, 27%), or cervical (n = 8, 6%). Primary tumor was resected for 85% (n = 106) with surgical nodal evaluation for 60% (n = 75). Systemic therapy, most commonly immune checkpoint inhibitors (ICI, 58% systemic therapy), was used to treat all except one unresectable patient (17/18) and 33% (35/106) of resectable patients. Seven patients received neoadjuvant ICI. Fourteen patients received adjuvant radiation therapy to the pelvis (RT, 13% of those undergoing resection). With a median follow-up of 45 months, 100 patients (81%) recurred. Four-year actuarial outcomes were: 46% local control, 53% nodal control, 36% distant metastasis-free survival, 17% disease-free survival, 49% melanoma-specific survival and 48% overall survival. Mitotic rate > 10/mm2, nodal involvement and non-vulvar anatomic subsite were associated with poor outcomes. Patients treated after 2016 did not have significantly better outcomes than those treated earlier. Patients with GTM continue to have poor outcomes in the contemporary therapeutic era with particularly notable poor local disease control relative to other mucosal melanoma subtypes. More effective oncologic therapy is needed. • Gynecologic tract melanoma patients continue to have poor outcomes in the contemporary therapeutic era. • About half of patients will have primary disease progression with almost two-thirds developing distant metastasis. • High mitotic rate and vaginal or cervical disease predict for worse outcomes. • Radiation therapy may play a role in improving local disease control. [ABSTRACT FROM AUTHOR]

We reviewed our institutional data to evaluate toxicity and efficacy outcomes of pembrolizumab/lenvatinib in recurrent endometrial cancer in a "real-world" clinical setting and to compare the impact of reduced lenvatinib starting dose on outcomes. Retrospectively, we reviewed toxicity, treatment responses, and survival outcomes of patients with recurrent endometrial cancer who received ≥1 cycle of pembrolizumab/lenvatinib. We compared subgroups based on lenvatinib starting dose (recommended [20 mg] vs reduced [<20 mg]) and histologic type. We analyzed 70 patients (recommended dose cohort, n = 16; reduced dose cohort, n = 54). The most common starting dose was 14 mg daily. Compared to the reduced dose cohort, the recommended dose cohort had a significantly higher mean number of lenvatinib dose reductions due to side effects (1.1 vs. 0.4; p = 0.003) and significantly shorter median time to treatment toxicity (1.3 vs. 3.7 days; p = 0.0001). Response rates did not differ significantly between the recommended and reduced dose cohorts (28.6% vs. 38.3%, respectively; p = 0.752). Two patients, both in the reduced dose cohort, had complete responses. Patients with carcinosarcoma histology had response and clinical benefit rates of 25% (3 of 12) and 58.3% (7 of 12), respectively. There were no differences between the 2 dose cohorts with respect to progression-free (p = 0.245) or overall survival (p = 0.858). In clinical practice, a lower starting dose of lenvatinib (14 mg daily) in combination with pembrolizumab was safe and efficacious in recurrent endometrial cancer. The combination produced responses in endometrial carcinosarcomas. Larger studies are required to validate these findings. • Recommended 20 mg lenvatinib dosage may be challenging for endometrial cancer patients to tolerate in clinical practice. • Compared to the recommended dose, a reduced lenvatinib starting dose had similar response rates in endometrial cancer. • Compared to the recommended dose, a reduced lenvatinib starting dose had less toxicity with similar survival outcomes. • For endometrial carcinosarcoma (not included in KEYNOTE-146/Study 111), the overall response rate was 25%. [ABSTRACT FROM AUTHOR]

To investigate the efficacy and safety of pembrolizumab in women with recurrent small cell neuroendocrine tumors of the lower genital tract. We conducted an open-label, investigator-initiated phase II basket trial of pembrolizumab 200 mg intravenously every 3 weeks in patients with rare tumors (ClinicalTrials.gov : NCT02721732). The trial had prespecified cohorts, including small cell malignancies of extrapulmonary origin. Eligibility criteria included disease progression during standard treatment in the 6 months before study enrollment. Patients were enrolled from February 2017 to February 2019. The primary endpoint was the proportion of patients alive without progression at 27 weeks. Response to pembrolizumab was evaluated every 9 weeks (3 cycles) with radiographic imaging. Seven women with gynecologic extrapulmonary small cell carcinoma were enrolled, 6 with cervical and 1 with vulvar carcinoma. No patient was progression free at 27 weeks. At first radiologic assessment, 1 patient had stable disease, while 6 had progression. The single patient with stable disease at 6 weeks had disease progression at 14 weeks. The median progression-free interval was 2.1 months (range 0.8–3.3 months). Severe treatment-related adverse events (≥grade 3) were seen in 2 of 7 patients (29%); 1 patient had grade 3 asymptomatic elevation of serum alkaline phosphatase, and 1 had grade 3 asymptomatic elevation of serum alanine aminotransferase. Pembrolizumab alone showed minimal activity in women with recurrent small cell neuroendocrine tumors of the lower genital tract. Treatment was well tolerated in the majority of study participants, and the rate of severe adverse events was low. • Single-agent pembrolizumab had minimal antitumor activity against small cell neuroendocrine tumors of the gynecologic tract. • Single-agent pembrolizumab had acceptable toxicity in patients with small cell neuroendocrine tumors of the gynecologic tract. • Primary small cell neuroendocrine tumors of the gynecologic tract were associated with low PD-L1 expression. [ABSTRACT FROM AUTHOR]

Patients with persistent/recurrent cervical cancer following platinum-based chemotherapy have limited therapeutic options. The Gynecologic-Oncology-Group conducted a phase II trial to assess efficacy and tolerability of nivolumab, an immune checkpoint inhibitor, in persistent/recurrent cervical carcinoma. Key eligibility criteria included persistent/recurrent cervical cancer, failure of prior systemic therapy and ECOG PS 0-1. Nivolumab 3 mg/kg was given IV every 2 wk. until disease progression or intolerable toxicity. Response was assessed every 8 wk. for 6 months and every 12 wk. thereafter. The primary endpoints were objective response as assessed by RECIST 1.1. The study used a 2-stage group sequential design. PD-L1 expression was evaluated in tumor specimens by immunohistochemistry (IHC) using a combined-positive-score (CPS) cutoff of ≥1%. Of 26 enrolled patients with persistent/recurrent cervical cancer, 25 were evaluable for response/toxicity with a median age of 45. 36% had ECOG PS of 1, and 100% had received one prior systemic chemotherapy regimen. PD-L1 expression (≥1%) was identified in 77.3% of tumor samples. As of 03/05/19, all patients were off study treatment; median follow-up for survival status was 32 months (range, 2–41.5). There were 21 (84%) patients with a treatment-related adverse event (TRAE) and most were grades 1–2. Six (24%) patients had grade 3 TRAEs with 1 discontinuing nivolumab due to hepatic toxicity. No grade 5 TRAEs occurred, and 2 patients had grade 4 TRAEs. One confirmed partial response (4%; 90% CI, 0.4%–22.9%), duration of response 3.8 months. Thirty-six percent of patients had stable disease (SD) (9/25; 90% CI, 20.2%–54.4%); the median duration of SD was 5.7 months (range, 3.5–12.7). Estimated PFS and OS at 6 months were 16% and 78.4%, respectively. Single agent nivolumab exhibited low antitumor activity and an acceptable safety profile in patients with persistent/recurrent cervical cancer previously treated with platinum-based chemotherapy. • Cervical cancers are infected with Human Papillomavirus (HPV) making these tumors potentially immunogenic. • NRG-GY002 evaluated the activity of single agent nivolumab in persistent or recurrent cervical cancer patients. • Nivolumab has an acceptable safety profile but low antitumor activity in cervical cancer. • Combinations of immune check-point inhibitors may be necessary to increase clinical responses in cervical cancer. [ABSTRACT FROM AUTHOR]

Objective Our objective was to characterize the intra and peritumoral immune profile in recurrent cervical cancers to identify rational immunotherapy targets. Methods Archival pelvic exenteration specimens were examined using a validated multiplex immuno-fluorescent panel of antibodies against cluster of differentiation 8 (CD8), cluster of differentiation 68 (CD68), forkhead box P3 (FoxP3), programmed cell death protein 1 (PD1), and programmed death-ligand 1 (PD-L1, N = 28). Clinical data were abstracted from the electronic medical record. Results Cytotoxic T cells, macrophages, and regulatory T cells were found in higher densities in peritumoral stroma (CD8 + density 497.7 vs 83.5, p < 0.0001, CD68 + density 345.0 vs 196.7, p = 0.04, FoxP3 + density 214.5 vs 35.6, p < 0.0001). Antigen experienced T cells (PD1 +) were higher in peritumoral compared to tumor tissue (median normalized fluorescence intensity 0.05 vs 0.0085, p < 0.001). Although there was a higher median density of intratumoral cytotoxic T cells and macrophages compared to regulatory T cells (median density CD8 + 83.5 vs 35.6, p < 0.05, median density 196.7 vs 35.6, p < 0.05), the presence of macrophages correlated with the presence of regulatory T cells in tumors ( r = 0.58, p = 0.001). Conclusions While cytotoxic T cells are present in tumor tissue to varying degrees, their density is lower than in peritumoral stroma, suggesting intratumoral exclusion or destruction of T cells. Higher densities of intratumoral macrophages compared to regulatory T cells suggest macrophages may be important contributors to the immunosuppressive tumor environment. Future directions for combination therapy include altering T cell trafficking and targeting tumor associated macrophages (TAMs) to enhance intratumoral activated T cell density and effect a more robust immune response. [ABSTRACT FROM AUTHOR]

Single agent immune checkpoint blockade (ICB) has demonstrated response rates of 5-15% in patients with recurrent high-grade ovarian cancer (HGOC), with another 15-40% of patients achieving stable disease. Combination ICB using ipilimumab and nivolumab resulted in improved response rates in a mixed population with platinum resistant and sensitive disease. The objective of the current trial was to evaluate sequential versus combination CTLA4 and PDL1 blockade strategies for extending progression free survival (PFS) in patients with platinum resistant/refractory HGOC. Patients were required to have pathologically confirmed platinum resistant or refractory epithelial ovarian cancer, no prior immunotherapy, and PS= 0-1 for enrollment. The current abstract includes data only on subjects with high grade serous ovarian cancer (HGSOC), as enrollment of patients with clear cell histology is still ongoing. The primary endpoint was PFS and response was assessed using modified RECIST v1.1. Unlimited numbers of prior regimens were allowed. Patients were adaptively randomized to sequential arm: tremelimumab (3mg/kg q4 weeks x 4 doses) followed by durvalumab (1.5g IV q4 weeks for up to 9 doses) upon progression, or the combination arm: tremelimumab (1mg/kg IV plus durvalumab 1.5g IV q4wk for up to 4 doses followed by durvalumab monotherapy for up to 9 doses). For the Bayesian adaptive randomization, the probability of being assigned to an arm was proportional to the likelihood the arm had better PFS, such that patients were more likely to be randomized to the more effective arm. A total of 61 subjects were adaptively randomized to sequential treatment (n=38) or combination therapy (n=23). 46 (79%) patients had wild-type breast cancer gene (BRCA). Median prior lines of therapy was 4 (range: 1-10). There was no difference in median PFS in the sequential arm (1.84 months; 95% CI: 1.77 – 2.17)) compared with the combination arm (1.87 months; 95% CI: 1.77 – 2.43), p=0.402. Similarly, median OS in the sequential and combination arms were 10.61 months (5.95 – 15.34) and 7.26 (4.24 – 15.57), respectively (p=0.810). In the sequential arm no objective responses were observed, although 12 patients (31.6%) exhibited stable disease. In the combination arm, 2 patients had partial response (8.7%) while one additional patient (4.4%) had stable disease. The adverse event profile was consistent with that previously reported for immune checkpoint therapy. [Display omitted] There was no difference in the median PFS between the combination and sequential durvalumab plus tremelimumab treatment strategy arms in a heavily pretreated population of patients with platinum resistant/refractory HGOC. Response rates were comparable to prior reports, though the combination regimen did not add significant benefit as has been previously described with combination of ipilimumab/nivolumab. Further exploration into subpopulations that may have increased benefit from ICB is warranted. [ABSTRACT FROM AUTHOR]