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Simple Summary: Renal medullary carcinoma (RMC) is an aggressive type of kidney cancer. Traditional treatments have limited effectiveness, so new strategies are needed. Studies of RMC tissues found signs of inflammation, suggesting that immune checkpoint therapies could be a potential treatment option. In this study, we tested the effectiveness of pembrolizumab, an immune checkpoint inhibitor in a group of patients with RMC. Unfortunately, the results showed that pembrolizumab did not stop tumor growth. All the patients experienced rapid disease progression. One patient had such rapid progression that they had to stop the treatment less than a week after receiving pembrolizumab. In conclusion, this study demonstrated that pembrolizumab did not show any clinical benefits in patients with RMC. Background. Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and immune profiling of RMC tissues revealed a highly inflamed phenotype, suggesting the potential therapeutic role for immune checkpoint therapies. We present the first prospective evaluation of an immune checkpoint inhibitor in a cohort of patients with RMC. Methods. A cohort of patients with locally advanced or metastatic RMC was treated with pembrolizumab 200 mg intravenously every 21 days in a phase II basket trial (ClinicalTrials.gov: NCT02721732). Responses were assessed by irRECIST. Tumor tissues were evaluated for PD-L1 expression and for tumor-infiltrating lymphocyte (TIL) levels. Somatic mutations were assessed by targeted next-generation sequencing. Results. A total of five patients were treated. All patients had advanced disease, with the majority of patients (60%) having metastatic disease at diagnosis. All patients had rapid disease progression despite pembrolizumab treatment, with a median time to progression of 8.7 weeks. One patient (patient 5) experienced sudden clinical progression immediately after treatment initiation and was thus taken off trial less than one week after receiving pembrolizumab. Conclusions. This prospective evaluation showed no evidence of clinical activity for pembrolizumab in patients with RMC, irrespective of PD-L1 or TIL levels. [ABSTRACT FROM AUTHOR]

Patients with rare solid tumors treated on early phase trials experience toxicities from their tumors and treatments. However, limited data exist to describe the detailed symptom burden suffered by these patients, particularly those with rare solid tumors treated with immunotherapy. We performed a prospective longitudinal study to capture patient-reported symptom burden. Patients completed the validated MD Anderson Symptom Inventory (MDASI)—Immunotherapy with 20 symptoms including 7 immunotherapy-specific items and 6 interference items at baseline and weekly thereafter for up to 9 weeks. Symptoms and interference were rated on 0–10 scales (0 = none or no interference, 10 = worst imaginable or complete interference). Group-based trajectory modelling determined higher and lower symptom groups. A total of 336 MDASI questionnaires were completed by 53 patients (mean age 55.4y, 53% male) with advanced rare cancers receiving pembrolizumab in a Phase II clinical trial. Symptoms reported as most severe over the course of the treatment over 9 weeks were fatigue [mean (M) = 3.8, SD = 2.3], pain (M = 3.7, SD = 2.9), disturbed sleep (M = 2.7, SD = 2.3), drowsiness (M = 2.6, SD = 2.0) and lack of appetite (M = 2.5, SD = 2.1). Pain in the abdomen (M = 2.2, SD = 2.4), rash (M = 1.1, SD = 1.8) and diarrhea (M = 0.9, SD = 1.5) were less severe. Interference with walking was rated the highest (M = 3.4, SD = 2.8) and relations with others was rated the lowest (M = 2.1, SD = 2.6). Using a composite score based on the five most severe symptoms (fatigue, pain, lack of appetite, feeling drowsy and sleep disturbance), 43% were classified into the high symptom burden group. Using a score based on immunotherapy-specific symptoms (e.g., rash, diarrhea) 33% of patients were included in the high symptom group. Symptom burden stayed relatively stable in the high- and low-symptom burden patient groups from baseline through 9 weeks. Some patients with rare malignancies experienced high symptom burden even at baseline. In patients with rare cancers, symptom trajectories stayed relatively stable over nine weeks of treatment with pembrolizumab. Trial registration: ClinicalTrials.gov identifier: NCT02721732. [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]

Summary: Background. Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies. Methods. This was a single-center, multi-arm phase Ib study utilizing a "basket type" expansion. CT and selinexor was employed as one of the 13 parallel arms. Advanced relapsed/refractory solid tumors following standard therapy or where the addition of selinexor to standard regimens deemed appropriate, were eligible. Results. Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n = 4), esophageal (n = 2), ovarian (n = 2) and non-small cell lung cancers (n = 2). All 13 patients had at least one treatment-related adverse events (TRAEs) and the most common were neutropenia (85%), leukopenia (85%), thrombocytopenia (85%), anemia (69%), nausea (54%), vomiting (46%), and fatigue (46%). One patient at 60 mg QW experienced DLT with grade 3 nausea and vomiting lasting 3 days. Unconfirmed partial response (uPR) was observed in 3 patients; one patient each with esophageal, breast, and ovarian cancer. One patient with esophageal adenocarcinoma had confirmed PR, however, was discontinued from the study due to clinical progression. Five patients achieved stable disease (SD). Disease control rate was 8%. Majority of patients (77%), including two patients who had uPR, had prior exposure to carboplatin and/or paclitaxel. Time-to-treatment failure (TTF) ranged from 1 to 153 weeks. Conclusion. The RP2D of selinexor was 60 mg QW in combination with CT. The combination conferred viable clinical activity with durable objective responses which should further be explored in tumor types for which CT is used as standard of care. Trial information. ClinicalTrials.gov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495). [ABSTRACT FROM AUTHOR]

Summary: Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3–10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population. [ABSTRACT FROM AUTHOR]

Background Immunotherapy is emerging as the cornerstone for treatment of patients with advanced cancer, but significant toxicity (immune-related adverse events [irAEs]) associated with unbridled T cell activity remains a concern. Patients and methods A retrospective review of the electronic medical records of 290 patients with advanced cancer treated on an immunotherapy-based clinical trial in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center between February 2010 and September 2015 was performed. Clinical and laboratory parameters were collected to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. Results Ninety eight of 290 patients (34%) experienced any grade irAEs. Among the 15 (5.2%) patients with grade ≥ 3 irAEs, the most common irAEs were dermatitis and enterocolitis. Although 80% of the patients with grade ≥ 3 irAEs required systemic corticosteroids, all the 15 patients recovered from the irAEs. On re-challenge, 4 of the 5 patients who had received systemic corticosteroids for irAE continued to respond. There were no irAE-related deaths. Importantly, patients with grade ≥ 3 irAEs had improved overall response rate (25 vs. 6%; p = 0.039) and longer median time to progression (30 weeks vs. 10 weeks; p = 0.0040) when compared to those without grade ≥ 3 irAEs. Conclusion Incidence of irAEs with immunotherapeutic agents indicates an active immune status, suggestive of potential clinical benefit to the patient. Further validation of this association in a large prospective study is warranted. [ABSTRACT FROM AUTHOR]

Purpose Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors. Patients and Methods Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity). An expansion cohort selected for patients with molecular alterations in the PI3K/AKT/mTOR pathway. Results Sixty-two patients were enrolled; median age was 60 years; 29 were women. The MTD was pazopanib 600 mg every other day (QOD) alternating with everolimus 10 mg PO QOD. DLTs were grade 3 thrombocytopenia and creatinine elevation. Most common toxicities of any grade were thrombocytopenia, transaminitis, leukopenia/neutropenia and lipid abnormalities. Among 52 patients evaluable for response, the clinical benefit rate (CBR) was 27 % (14/52) including four partial responses (PR), and 10 stable disease (SD) ≥6 months. 26 of 45 patients evaluated for molecular alterations had at least one alteration in the PI3K/AKT/mTOR pathway. CBR in patients with a matched alteration was 27 % (7/26) versus 26 % (5/19) for patients without an alteration ( p = 0.764). However, 64% of those with CBR and molecular testing done for alteration in the PI3K/AKT/mTOR pathway were positive. Conclusion Combination treatment with pazopanib and everolimus was well tolerated and demonstrated activity in solid tumors. Further exploration of this combination and molecular correlation with treatment outcomes is warranted. [ABSTRACT FROM AUTHOR]

The immune checkpoint inhibitors (ICIs) entered treatment algorithms in most tumors. However, the data on the efficacy is limited in rare tumors with no phase III studies. We systemically reviewed the clinical trials evaluating the ICI efficacy in rare tumors and included a total of 47 clinical trials in this review. The ICIs demonstrated over 30% response rates in Merkel cell carcinoma and squamous cell carcinoma of the skin and became the standard of care. Additionally, the ICI efficacy was promising in thymic epithelial tumors and gestational trophoblastic neoplasia. In contrast, the ICI efficacy is limited in most sarcomas, germ cell tumors and low-grade neuroendocrine tumors. The ICI efficacy seemed to be improved with combinations targeting tumor microenvironment in sarcomas. The available evidence on ICI efficacy in rare tumors denote a need for better patient selection and novel combination strategies to improve outcomes. [Display omitted] • The developments with immunotherapy in rare tumors are relatively slow. • Immunotherapy has promising activity in MCC and skin SCC. • The efficacy is limited in most sarcoma types, germ cell tumors, and low-grade NETs. • The biomarker data is limited and unequivocal. • Studies focusing on novel combination strategies and biomarkers are urgently needed. [ABSTRACT FROM AUTHOR]

Metastatic pheochromocytomas and paragangliomas (MPPGs) are rare endocrine malignancies that are associated with high rates of morbidity and mortality because of their large tumor burden and location, progression, and release of catecholamines. Systemic therapies for MPPGs are limited. MPPGs are characterized by pseudohypoxia that may prevent immune system recognition. We conducted a phase II clinical trial of pembrolizumab in patients with progressive MPPGs. The primary endpoint was the non-progression rate at 27 weeks. The secondary endpoints included the objective response and clinical benefit rates, progression free and overall survival duration, and safety. We also determined whether PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor were associated with clinical response and hereditary background. Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors. Four patients (40%, 95% confidence interval (CI) 12–74%) achieved the primary endpoint. The objective response rate was 9% (95% CI: 0–41%). The clinical benefit rate was 73% (95% CI: 39–94%). Four patients had grade 3 adverse events related to pembrolizumab. No patients experienced grade 4 or 5 adverse events or a catecholamine crisis. Progression free survival time was 5.7 months (95% CI: 4.37—not reached). The median survival duration was 19 months (95% CI: 9.9—not reached). PDL-1 expression and the presence of infiltrating mononuclear inflammatory cells in the primary tumor did not seem to be associated with disease response. Single-agent pembrolizumab has modest treatment efficacy in patients with progressive MPPGs. Positive responses seemed to be independent of patients' hereditary backgrounds, tumor hormonal status, and the presence of infiltrating mononuclear inflammatory cells or PDL-1 expression in the primary tumor. [ABSTRACT FROM AUTHOR]

Background: Adrenocortical carcinoma (ACC) is a rare malignancy without good treatment options. There are limited data about the use of immunotherapy in ACC. We investigated the efficacy and safety of pembrolizumab in patients with metastatic ACC. Methods: This is a pre-specified cohort of a single-center, investigator-initiated, phase II clinical trial using pembrolizumab monotherapy in patients with rare malignancies. Patients must have had prior treatment fail in the past 6 months before study enrollment. Patients were enrolled from August 2016 to October 2018. Follow-up data were updated as of March 26, 2019. Patients received 200 mg pembrolizumab intravenously every 3 weeks without concomitant oncologic therapy. The primary endpoint was non-progression rate (NPR) at 27 weeks. Other endpoints included adverse events, tumor responses measured independently by objective radiologic criteria, and select immunological markers. Results: Sixteen patients with ACC (including eight women [50%]) were included in this cohort. Ten patients (63%) had evidence of hormonal overproduction (seven had cortisol-producing ACC). Non-progression rate at 27 weeks was evaluable in 14 patients, one patient was lost to follow-up, and one patient left the study because of an adverse event. Five of 14 patients were alive and progression-free at 27 weeks (non-progression rate at 27 weeks was 36, 95% confidence interval 13–65%). Of the 14 patients evaluable for imaging response by immune-related Response Evaluation Criteria in Solid Tumors, two had a partial response (including one with cortisol-producing ACC), seven had stable disease (including three with cortisol-producing ACC), and five had progressive disease, representing an objective response rate of 14% (95% confidence interval 2–43%). Of those who had stable disease, six had disease stabilization that lasted ≥4 months. Severe treatment-related adverse events (≥grade 3) were seen in 2 of 16 patients (13%) and resulted in one patient discontinuing study participation. All studied tumor specimens (14/14) were negative for programmed cell death ligand-1 expression. Thirteen of 14 tumor specimens (93%) were microsatellite-stable. Eight of 14 patients (57%) had a high tumor-infiltrating lymphocyte score on immunohistochemistry staining. Conclusions: Single-agent pembrolizumab has modest efficacy as a salvage therapy in ACC regardless of the tumor's hormonal function, microsatellite instability status, or programmed cell death ligand-1 status. Treatment was well tolerated in most study participants, with a low rate of severe adverse events. Trial registration: ClinicalTrials.gov identifier: NCT02721732, Registered March 29, 2016. [ABSTRACT FROM AUTHOR]