Clinical Trial Of Ipilimumab Research Articles

Abstract CT262: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: sarcomatoid carcinoma of lung (cohort 11)

Abstract Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in rare solid cancers is yet to be established. This study presents the first results of ipilimumab and nivolumab in the sarcomatoid carcinoma of lung cohort (#11) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Fourteen evaluable patients (median age, 64 years) with sarcomatoid carcinoma lung tumors were analyzed. ORR was 28.6% (4/14) with 1 CR and 3 PRs. The patient with CR has a duration of response (DoR) and OS of 32.4+ months. Three patients with PR showed 100% regression with resolution of one of two non-measurable non-target lesions (DoR 36.8 months), 92% regression (DoR 6.6 months), and 52% regression (DoR 23.0+ months), respectively. Clinical benefit rate (CBR; no progression > 6months) was 50.0% (7/14). The median PFS was 6.1 months, median OS was 10.9 months. The most common adverse events were fatigue and dyspnea (46.2%, n=6 each), and pruritus and hypothyroidism (30.8%, n=4 each). Grade 3-4 adverse events occurred in 30.8% of patients (n=4). There were no adverse events that led to discontinuation. There was one grade 5 adverse event due to respiratory failure. Conclusion: Ipilimumab plus nivolumab in sarcomatoid carcinoma of lung resulted in an ORR of 28.6% and CBR (SD>6 months/PR/CR) of 50.0%, with PFS of 36.9, 32.4+, 23.0+, 17.0, 13.3, 6.6, and 6.6 months. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies are warranted. Citation Format: Young Kwang Chae, Megan Othus, Sandip Patel, Peeran Sandhu, Larry R. Corum, Jeremy P. Cetnar, Shayan Rayani, Anna Moseley, Liam Il-Young Chung, Hye Sung Kim, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: sarcomatoid carcinoma of lung (cohort 11) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT262.

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The desmoid tumors (cohort 27).

11516 Background: Dual inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors is efficacious in many malignancies, but their potential role in numerous rare solid cancers is yet to be established. Desmoid tumors (DT; fibromatosis) are rare tumors of the soft tissue, and the mainstay of treatment is surgery (Richard Riedel, 2022). The utility of immunotherapy in this group of patients has not been explored. This study presents the first results of ipilimumab and nivolumab used in the DT cohort (#27) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint includes objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)). Secondary endpoints include progression-free survival (PFS), overall survival (OS), stable disease (SD) > 6 months, and toxicity. Results: Sixteen evaluable patients (median age 37) with desmoid tumors were analyzed. Location of the tumors are: 8, abdomen; 3, lower limb: 2, upper limb; 2, pelvis; and 1, neck. ORR was 18.8% with 3 patients attaining PR: 40% regression with ongoing duration of response (DoR) at over 30+ months; 83% regression (PFS 16 months); and 71% regression (PFS of 8.4 months). Of note, 3 patients had SD (3/16, 18.8%) with some shrinkage of the tumors and a durable response; 23% regression with PFS of 1820+ days; 6% regression with PFS of 902 days; 1% regression with PFS of 1147+ days. Overall clinical benefit rate (CBR; no progression > 6 months) was 62.5%. The median PFS was 17.9 months, 6-month PFS 69%, 1-year PFS 62%. All patients were alive at 1 years; median OS was not assessable as 14 patients are showing ongoing survival. The most common adverse events were fatigue (43.8%, n = 7), nausea (37.5%, n = 6), hypothyroidism (31.3%, n = 5), diarrhea, hyperthyroidism, headache, and adrenal insufficiency (25%, n = 4 each). There were 8 incidents (50%) of grade 3-4 adverse events. 7 adverse events led to discontinuation. There were no grade 5 adverse events. Conclusions: Ipilimumab plus nivolumab in treatment of desmoid tumors resulted in an ORR of 18.8% and CBR of 62.5% with durable responses seen. This is the first prospective study demonstrating efficacy of the combination in this rare disease. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in desmoid tumors are needed. Clinical trial information: NCT02834013 .

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The vulvar cancers.

5517 Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in various rare solid cancers is yet to be established. The efficacy of immunotherapy in vulvar cancer patients has not been explored. This study presents the first results of ipilimumab and nivolumab in vulvar cancers (cohort 35) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) > 6 months, and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years) were analyzed. 14 cases were of squamous cell carcinoma histology and 2 were of poorly differentiated carcinoma. ORR was 18.8% (3/16, 25% when including one unconfirmed PR). There was 1 CR (SCC; PFS of 465 days) and 2 PR (both SCC; one with 57% regression with PFS of 1022 days, another with 53% regression with PFS of 501 days). Of note, there was one SCC patient with unconfirmed PR that showed 69% regression with PFS of 209 days. Overall clinical benefit rate (CBR; no progression > 6months) was 31.3% (5/16). The median PFS was 2.2 months, 6-month PFS 33%, 1-year PFS 20%. The median OS was 7.6 months, 6-month OS 62%, 1-year OS 44%. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3-4 adverse events occurred in 25% of patients (n = 4). There was 1 grade 3-4 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an ORR of 18.8% and CBR of 31.3%, with durable responses seen. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies exploring the role of immunotherapy in vulvar cancers are warranted. Clinical trial information: NCT02834013 .

Abstract CT161: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the non-epithelial ovarian tumor cohort

Abstract Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in numerous rare solid cancers is yet to be established. This study presents the first results of ipilimumab and nivolumab in the non-epithelial ovarian tumor cohort (#13) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). This cohort included several histologies grouped for statistical analysis. The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Seventeen evaluable patients (median age, 64 years) were analyzed. The subtypes of non-epithelial ovarian cancer were: granulosa cell (47%, n=8), carcinosarcoma or malignant mixed Mullerian tumor (MMMT; 35%, n=6), one each for Wolffian duct, yolk sac, and Sertoli-Leydig cell. There were 2 responses in the 8 patients with granulosa cell (ORR of 25% in the granulosa cell tumors): 1CR (79% regression [due to lymph node < 1.0cm], 59 month PFS, juvenile type) and 1 PR (79% regression, 51+ month PFS, adult type). 6/8 patients remain alive (PFS 52-1774 days). In contrast, carcinosarcomas showed no responses. One patient with Sertoli-Leydig cell tumor had a 22% response and 341 day PFS. Overall ORR was 12% (2/17), clinical benefit rate (CBR; no progression > 6months) of 29.4%. The median PFS was 3.5 months, median OS was 42.5 months. The most common adverse events were fatigue (52.9%, n=9) and hypothyroidism (35.3%, n=6). Grade 3-4 adverse events occurred in 47.1% of patients (n=8). There were 3 adverse events (17.6%) that led to discontinuation, of which 2 (11.8%) were grade 3-4. There were no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in non-epithelial ovarian cancer resulted in an ORR of 12% (with 2 of 8 patients with granulosa ovarian tumors showing a durable CR and PR [both, >4 years)) and CBR of 29.4%, with durable responses seen. In contrast there were no responses in the carcinosarcoma group. One patient with Sertoli Leydig cell tumor suggested a possible benefit. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in granulosa tumor but not carcinosarcoma are warranted. Citation Format: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Kelly J. Wilkinson, Emily M. Whitman-Purves, Jayanthi Lea, John M. Schallenkamp, Nabil Adra, Leonard J. Appleman, Mitchell Alden, Jessica Thomes Pepin, John A. Ellerton, Andrew Poklepovic, Adam Walter, Murtuza M. Rampurwala, William R. Robinson, Liam Il-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the non-epithelial ovarian tumor cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT161.

Abstract CT163: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the small cell carcinoma of the ovary, hypercalcemic type cohort

Abstract Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have shown to be efficacious in many malignancies, but its potential role in various rare solid cancers is yet to be established. Small cell ovarian carcinoma, hypercalcemic type (SCCOHT) is a rare tumor characterized by loss of SMARC 2/4 function and so presents a novel paradigm for the treatment of SWI/SNF pathway deficient tumors (Petar Jelinic et al., 2018; Marc Tischkowitz et al., 2020). This study presents the first results of ipilimumab and nivolumab used in the SCCOHT cohort (#49) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint includes objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)). Secondary endpoints include progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity. Results: Five evaluable patients (median age 30) with SCCOHT were analyzed. Objective response rate was 20% (1 CR with 100% regression). The patient with CR has a duration of response (DoR) and OS of 35+ months. Another patient, showed unconfirmed PR with 81% regression (DoR 4 months), this patient went on to have confirmed iCR (CR confirmed by iRECIST) at around 24 months and has OS of 38+ months. At 12 months, 3 patients remain alive and 1 patient remains progression free; overall median PFS was 1.8 months (1.0-∞); median OS was 24 months (4.5-∞). The most common adverse events were fatigue, nausea, pruritus, dry mouth, maculo-papular rash and aspartate aminotransferase elevation (50%, n=2, respectively). There were two incidents (33.3%) of grade 3-4 adverse events. None of the adverse events led to discontinuation. There were no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in five patients with the ultra-rare small cell ovarian carcinoma (hypercalcemic type) resulted in one CR durable at 35+ months and one unconfirmed PR with 81% regression. This is the first prospective study demonstrating efficacy of nivolumab and ipilimumab in this rare disease. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in small cell ovarian histologies are needed. Citation Format: Young Kwang Chae, Megan Othus, Sandip P. Patel, Raid Aljumaily, Khine Z. Win, Tanya Pejovic, Sajeve S. Thomas, William R. Robinson, Liam Il-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the small cell carcinoma of the ovary, hypercalcemic type cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT163.

Abstract CT162: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts

Abstract Background: Dual checkpoint inhibition with anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be efficacious in numerous malignancies. This study presents the first results of ipilimumab and nivolumab in the clear cell gynecologic cancer cohorts of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg IV every 6wk) plus nivolumab (240mg IV every 2wk). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed CR and PR); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Evaluable patients were as follows: clear cell ovarian cancer (N=19); clear cell endometrial cancer (N=8); clear cell cervical (N=5) (median ages, 53, 66, and 59 years; cohorts 46, 45, and 42, respectively) In the clear cell ovarian cancer cohort, ORR was 21.1% [CR, 15.8%, n=3; PR, 5.3%, n=1]; clinical benefit rate (CBR) (includes stable disease ≥6 months) was 31.6% (6/19 patients). Among three patients with confirmed CR, two patients showed 100% regression (with ongoing response at 36+ months and 37+ months respectively), and the other patient showed 67% regression (due to lymph node < 1.0cm), but eventually progressed after 722 days. One confirmed PR patient achieved 75% regression (ongoing response at 53+ months). Of note, three patients achieved unconfirmed PR; one showed 34% regression (5 months); another, 38% (51.5+ months); and another, 58% regression (5 months). The ORR when including unconfirmed PR is 36.8% (7/19). Median PFS was 3.7 months (95% confidence interval (CI); 1.7-∞). Median OS was 21.7 months (6.4-∞). In the clear cell endometrial cancer cohort, ORR was 0%; CBR, 25% (2/8 patients). Of note, one patient achieved unconfirmed PR with 69% regression (4 months). The ORR when including unconfirmed PR is 12.5% (1/8). Median PFS was 2.0 months (95% confidence interval; 1.8-na). Median OS was 4.3 months (4.2-na). In the clear cell cervical cancer cohort, ORR was 0%; CBR, 20.0% (1/5 patients). Median PFS was 2.2 months (95% CI; 1.9-na). Median OS was 23.6 months (95% CI; 15.3-na). The most common adverse events, in the three cohorts combined, were nausea (37.5%, n=12), fatigue (34.4%, n=11), anorexia (31.2%, n=10), hypothyroidism (31.2%, n=10), and pruritus (28.1%, n=9). Grade 3-4 adverse events were reported in 17 cases (53.1%) with no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in 19 clear cell ovarian cancer patients resulted in an ORR of 21.1% and CBR of 31.6%, with two durable CRs ongoing at 3+ years; CBR was 25% and 20%, respectively, in clear cell endometrial and cervical cohorts, with no objective responses, albeit with only 8 and 5 patients per cohort. Correlative studies to determine response/resistance markers are ongoing. Further prospective studies in rare gynecologic malignancies are warranted. Citation Format: Young Kwang Chae, Christopher W. Ryan, Naing Aung, William R. Robinson, Megan Othus, Elad Sharon, David M. O'Malley, Floortje J. Backes, Charles D. Blanke, Ramez N. Eskander, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT162.

Phase 2 trial of immunotherapy in tumors with CDK12 inactivation (IMPACT): Results from cohort A of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) receiving dual immune checkpoint inhibition (ICI).

103 Background: Prostate cancer with CDK12 inactivation represents a distinct subtype in mCRPC, tumors are characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens and increased tumor T cell infiltration. Retrospective experiences with ICI in CDK12 inactivation CRPC pts reported PSA and radiographic responses. We conducted a prospective multi-site clinical trial of ipilimumab and nivolumab in CDK12 inactivation or mutated cancers. Herein, we report our findings in the completed cohort A of men with mCPRC. Methods: Eligible pts had mCRPC (ongoing androgen deprivation therapy with serum testosterone £ 50 ng/dL) and putative CDK12 inactivation of function aberrations on any commercial or institutional CLIA/CAP approved next generation sequencing assay. Archival tumor tissue was requested for correlative biomarker analysis. Pts received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was PSA response, defined as a greater than or equal to 50% decline in PSA from baseline. Secondary endpoints included safety/toxicity, secondary efficacy measures including QoL and overall survival. Exploratory objectives included baseline tumor whole exome analysis and changes in circulating immune profiles with therapy. Results: As of data cut-off in Aug 2021, 28 mCRPC pts enrolled in Cohort A; median ECOG PS was 1 (0-2 range), 22/28 had Gleason 8-10 cancer, mean baseline PSA at study entry was 231 ng/dL, all pts had received ≥1 prior oral androgen signaling inhibitor and ≥1 cytotoxic chemotherapy. Unconfirmed PSA ≥30% decline was seen in 6/28 pts (21.4%) and PSA ≥50% decline in 4/28 pts (14.2%). Grade ≥3 possible/probable/definite adverse events were noted in 7/28 (25%) and SAEs in 10/28 pts (35.7%). Six pts (21.4%) experienced a rapid PSA increase by ≥ 10-fold over baseline. Conclusions: Combination immunotherapy was reasonably tolerated in this heavily pre-treated population and was associated with unconfirmed PSA responses in a subset of pts. Ongoing correlative analyses could explain responses mechanistically. Enrollment in Cohort B of non-prostate cancers and Cohort C of nivolumab monotherapy in prostate cancer are still ongoing. Clinical trial information: NCT03570619.

Abstract 3418: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The salivary gland tumor cohort

Abstract Background: Since their first approval in 2011 for metastatic melanoma, checkpoint inhibitors have been successfully applied to multiple tumor types. To date, the potential role for these treatments in rare solid tumors has not been well studied. We report the results of three salivary gland neoplasm cohorts of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: We performed a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks) in multiple tumor types. Here, we report the results found in three salivary gland neoplasm cohorts that include patients with salivary gland tumor types arising in major salivary glands (cohort 2), other sites of origin (cohort 3) and adenoid cystic carcinomas of any site (cohort 34). Primary endpoints included overall response rate (ORR) (RECIST v1.1) (complete response (CR) and partial responses (PR)); secondary endpoints included progression-free survival (PFS) and overall survival (OS), stable disease >6 months, and toxicity. Results: Twenty six patients with adenoid cystic salivary gland tumors and thirty five patients with other histologic subtypes of salivary gland neoplasm received therapy. The most common site of origin was the parotid (35%; N=9 in the adenoid cystic group and 54%; N=19 in the remaining histologies). The overall ORR in the adenoid cystic group was 4% (CR, 0%; PR, 4%, N= 1) and the median PFS was 4.4 months. 6 month OS was 84% and median OS was 12 months. In the remaining histologic subtypes the ORR was 9% (CR, 0%; PR, 9%, N=3) and the median PFS was 4.6 months. 6-month OS was 89%, median OS was not reached. The most common toxicities were fatigue (39%) and diarrhea (26%), with diarrhea (8%) as the most common grade 3-5 immune-related adverse event. Conclusions: In salivary gland tumors, combination therapy with ipilimumab plus nivolumab resulted in a 4% ORR in adenoid cystic carcinoma and 9% in other histologies combined. Citation Format: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, James P. Ohr, Francis P. Worden, Jennifer M. Suga, Aung Naing, Sarah E. Fenton, Hyunseok Kang, Sewan Gurung, Christine M. McLeod, Francis J. Giles, Helen X. Chen, Elad Sharon, Edward Mayerson, Melissa Plets, Christopher Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The salivary gland tumor cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3418.

Abstract 3417: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The small bowel tumor cohort

Abstract Background: The potential therapeutic benefits of checkpoint inhibitors and their application to many different tumor types has been a key factor in the advancement of medical oncology since their first approval for metastatic melanoma in 2011. However, their efficacy in rare tumor types remains to be seen. This paper presents the results of combination therapy with both anti-CTLA and anti-PD-1 in the small bowel cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART). Methods: This study is designed as a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks) in rare tumors. Here we report the outcomes from patients diagnosed with small bowel cancer (SBC). The primary endpoints included overall response rate (ORR) (RECIST v1.1) (complete response (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity were the secondary endpoints. Results: Twenty five patients were registered to the cohort and twenty three received therapy. The duodenum was the primary site of origin in 52% (N=11), 14% (N=3) arose in the ileum and 14% (N=3) arose in the jejunum. The primary site of origin was unknown in 19% (N=4). The overall response rate was 8% (CR, 4%, N= 1; PR, 4%, N= 1). The median PFS was 2 months; 6-month OS was 48% and median OS 6 months. The most common toxicities were diarrhea and fatigue (both 17%) followed by dyspnea (13%) with diarrhea, increased bilirubin, colitis and elevated lipase (all 4.3%) as the most common grade 3-5 immune-related adverse events. Conclusions: Combination therapy with ipilimumab plus nivolumab in small bowel tumors resulted in an overall response rate of 8% with one partial and one complete response in twenty three treated patients. Citation Format: Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Mark Zalupski, Anup Kasi, Maged Khalil, Aparna Kalyan, Blase Polite, Sarah Fenton, Sewan Gurung, Christine M. McLeod, Francis Giles, Helen X. Chen, Elad Sharon, Edward Mayerson, Melissa Plets, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The small bowel tumor cohort [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3417.

Abstract CT039: A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort

Abstract Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in metastatic rare solid tumors. We report here the results of the neuroendocrine cohort of SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART). Methods: We performed a prospective, open-label, multicenter phase 2 clinical trial of ipilimumab (1mg/kg q6 weeks) plus nivolumab (240mg intravenously every 2 weeks) across multiple cohorts of rare tumors, with the neuroendocrine cohort reported here. Pancreatic neuroendocrine tumors are currently being accrued to a separate cohort of S1609. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) >6 months, and toxicity. Results: Thirty-three eligible patients received therapy; 58% (N= 19) had high-grade disease; most common sites were gastrointestinal (non-pancreatic) (45%; N = 15) and lung (18%; N = 6). Patients had received a median of 2 lines of prior therapy. The overall response rate was 24% (CR, 3%; PR, 21%). Patients with high-grade neuroendocrine cancer had a 42% (8 of 19 patients) response rate vs. 0% in low/intermediate grade tumors (0/14 patients; p = 0.01). The 6-month PFS was 30%; median OS was 11 months. The most common toxicities were fatigue (30% of patients) and nausea (27%). Alanine aminotransferase (ALT) elevation (9%) was the most common grade 3-4 irAE, with no grade 5 toxicities. Conclusions: Ipilimumab plus nivolumab was well tolerated with a 42% ORR in patients with high-grade neuroendocrine cancer, regardless of primary site. Further investigation of this combination is warranted. Best Response Summary in 33 Patients with Neuroendocrine CancerResponse TypeAll Patients (n=33)High grade (n=19)Low/Intermediate grade (n=14)Complete Response (CR)1 (3%)1 (5%)0Partial Response (PR)7 (21%)7 (37%)0Stable Disease (SD)>6months2 (6%)02 (14%)SD11 (33%)3 (17%)8 (57%)Progressive Disease (PD)12 (36%)8 (42%)4 (29%)CR+PR8 (24%)8 (42%)0CR+PR+SD>6mo10 (30%)8 (42%)2 (14%) Citation Format: Sandip Pravin Patel, Megan Othus, Young Kwang Chae, Francis Giles, Donna Hansel, Preet Singh, Annette Fontaine, Manisha Shah, Anup Kasi, Tareq Al Baghdadi, Marc Matrana, Zoran Gatalica, W. Michael Korn, Jourdain Hayward, Christine MMcLeod, Helen X. Chen, Elad Sharon, Edward Mayerson, Christopher W. Ryan, Melissa Plets, Charles D. Blanke, Razelle Kurzrock. A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT039.

A Phase 1 Clinical Trial of Ipilimumab, Nivolumab and Radiation Therapy for Patients with Metastatic Melanoma

Combined blockade of immune checkpoints CTLA-4 and PD-1 with ipilimumab and nivolumab (ipi/nivo) represents the most effective strategy for the systemic treatment of metastatic melanoma. Preclinical studies suggest that tumor radiation therapy (RT) may modulate immune response in conjunction with ipi/nivo, and that the dose-fractionation of RT is relevant to this effect. This study was designed to assess the safety of combining ipi/nivo with 2 different RT dose-fractionation regimens: lower dose, conventionally-fractionated RT (Cohort A) and higher dose, hypofractionated RT (Cohort B). The hypothesis for this study is that the combination of ipi/nivo and RT is safe in metastatic melanoma. After IRB approval, a prospective, single-arm, two-cohort, Phase 1 clinical trial (NCT02659540) was initiated at 2 cancer centers. Eligible patients had ≥2 sites of metastatic melanoma: ≥1 site was amenable to RT and ≥1 site was observed for response by RECIST v1.1. Patients (n=9 per cohort) were enrolled in 2 consecutive cohorts (Cohort A, RT 30 Gy/10 fractions; Cohort B, RT 27 Gy/3 fractions) and started RT between the first and second doses of ipi/nivo given at the FDA-approved dose and schedule. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 24 weeks of the first dose of ipi/nivo were characterized according to CTCAE v4.03. Exploratory analyses of irradiated tumor and overall objective response rate (ORR, exclusive of the irradiated tumor) were performed in patients who received at least one dose of ipi/nivo and RT. In Cohort A, 10 patients (median age: 65 [range: 28-86] years; 6 female) were enrolled because 1 patient withdrew consent after ipi/nivo/RT, but before disease assessment. Grade 3-4 TEAEs were observed in 7/10 patients, while Grade 3-4 TRAEs were observed in 4/10 patients and included pruritus, anemia, thrombocytopenia, and lipase elevation. Irradiated tumor ORR was 44% (95% confidence interval [CI]: 14-79%), and ORR outside of the irradiated tumor was 44% (95% CI: 14-79%), with 2 patients dying of disease progression. Cohort B has enrolled 5 of 9 patients; safety and efficacy analyses are anticipated to be complete at the time of presentation. This is the first prospective clinical trial to report on the combination of ipi/nivo and RT. Despite the small number of planned accruals in this Phase 1 trial, the TRAE rate after ipi/nivo/lower dose, conventionally-fractionated RT was similar to what has been observed after ipi/nivo without RT, suggesting this regimen is safe. Further analyses will be required to better characterize the safety and efficacy of this regimen in Cohort B, as well as potential immunologic differences between the two RT cohorts in this study.

Bilateral drug (ipilimumab)-induced vitritis, choroiditis, and serous retinal detachments suggestive of vogt-koyanagi-harada syndrome.

To report a case of bilateral drug (ipilimumab)-induced vitritis, choroiditis, and serous retinal detachments suggestive of Vogt-Koyanagi-Harada syndrome. This is a single case report. A 43-year-old woman with metastatic melanoma reported a 1-day history of blurry vision after starting a phase 1 clinical trial of ipilimumab, a cytotoxic T lymphocyte-associated antigen 4 blocker, 2 weeks before presentation. Fundus examination of both eyes showed bilateral serous detachments with associated vitritis and choroiditis. Optical coherence tomography confirmed the presence of serous detachments, and fluorescein angiography demonstrated multiple areas of pinpoint leakage at the level of the retinal pigment epithelium. Treatment with high-dose corticosteroids led to a rapid improvement in vision and resolution of her serous detachments. Ten weeks after initial presentation, the patient developed vitiligo and poliosis. Vogt-Koyanagi-Harada syndrome is a bilateral granulomatous panuveitis associated with dermatologic, neurologic, and audiologic manifestations of yet an unclear pathogenesis. To our knowledge, we report the first case of ipilimumab treatment resulting in the acute presentation of bilateral vitritis, choroiditis, and serous detachments suggestive of Vogt-Koyanagi-Harada syndrome, which has particular significance because it may corroborate previous research attempting to elucidate the underlying mechanism of the disease.