Abstract
Background: The authors previously reported the results of the nonpancreatic neuroendocrine neoplasm cohort of the SWOG S1609 DART (Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors) trial, which permitted all histologic grades and had a 44% overall response rate (ORR) among patients with high-grade disease. Here they sought to validate their findings in a dedicated prospective cohort of high-grade neuroendocrine neoplasms within S1609. Methods: A prospective, open-label, multicenter, phase 2 clinical trial of ipilimumab plus nivolumab was conducted across multiple rare tumor cohorts. The dedicated, high-grade neuroendocrine neoplasm cohort was examined here. The primary end point was the ORR according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Nineteen patients with high-grade neuroendocrine neoplasms (defined by local pathology review) were enrolled in this cohort of S1609. The most common primary sites were unknown primaries (21%), which were followed by the rectum, gastroesophageal junction, cervix, and pancreas (11%). The median number of lines of prior therapy was 1 (range, 0-3). All patients were microsatellite-stable. The median Ki-67 value was 80%. The ORR was 26% (95% confidence interval [CI], 11%-45%), and the clinical benefit rate (stable disease for ≥6 months plus partial responses plus complete responses) was 32% (95% CI, 13%-57%). The 6-month PFS rate was 32% (95% CI, 16%-61%) with a median PFS of 2.0 months (95% CI, 1.8 months to ∞) and a median OS of 8.7 months (95% CI, 6.1 months to ∞). The most common toxicities were fatigue (32%) and rash (26%), and the most common grade 3/4 immune-related adverse event was rash (15%); there were no events that required treatment discontinuation and no grade 5 events. Conclusions: Ipilimumab plus nivolumab demonstrated a 26% ORR in patients with high-grade neuroendocrine neoplasms, with durable responses seen in patients with refractory disease.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3194-3201 |
| Number of pages | 8 |
| Journal | Cancer |
| Volume | 127 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2021 |
Keywords
- Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART)
- S1609
- high-grade neuroendocrine neoplasms
- ipilimumab
- nivolumab
ASJC Scopus subject areas
- Oncology
- Cancer Research
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A phase II basket trial of Dual Anti–CTLA–4 and Anti–PD–1 Blockade in Rare Tumors (DART) SWOG S1609 : High-grade neuroendocrine neoplasm cohort. / Patel, Sandip Pravin; Mayerson, Edward; Chae, Young Kwang et al.
In: Cancer, Vol. 127, No. 17, 01.09.2021, p. 3194-3201.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - A phase II basket trial of Dual Anti–CTLA–4 and Anti–PD–1 Blockade in Rare Tumors (DART) SWOG S1609
T2 - High-grade neuroendocrine neoplasm cohort
AU - Patel, Sandip Pravin
AU - Mayerson, Edward
AU - Chae, Young Kwang
AU - Strosberg, Jonathan
AU - Wang, Jue
AU - Konda, Bhavana
AU - Hayward, Jourdain
AU - McLeod, Christine M.
AU - Chen, Helen X.
AU - Sharon, Elad
AU - Othus, Megan
AU - Ryan, Christopher W.
AU - Plets, Melissa
AU - Blanke, Charles D.
AU - Kurzrock, Razelle
N1 - Funding Information: Sandip Pravin Patel reports that his university receives research grants from Bristol‐Myers Squibb, Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance; he also reports personal fees from Amgen, AstraZeneca, BeiGene, Bristol‐Myers Squibb, Certis, Eli Lilly, Genentech, Illumina, Merck, Novartis, Pfizer, Rakuten, and Tempus. Young Kwang Chae reports research grants from AbbVie, Bristol‐Myers Squibb, Biodesix, Lexent Bio, and Freenome and consulting fees, payments, and/or honoraria from Roche/Genentech, AstraZeneca, Bristol‐Myers Squibb, Foundation Medicine, Counsyl, Guardant Health, Boehringer Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, Pfizer, Tempus, Lunit, and Takeda. Bhavana Konda reports research funding to her institution from Bristol‐Myers Squibb, Xencor, Merck, Eisai, and Eli Lilly & Co. Elad Sharon is a full‐time employee of the National Cancer Institute. Christopher W. Ryan reports clinical trial support paid to his institution from Argos, Bristol‐Myers Squibb, CytRx, Daiichi‐Sankyo, Exelixis, Genentech, Novartis, Karyopharm, Merck, Nektar, Pfizer, TRACON, and Xynomic and consulting fees from AstraZeneca, Bristol‐Meyer Squibb, Deciphera, Exelixis, Eisai, Janssen, and Daiichi‐Sanyo. Razelle Kurzrock reports research funding from Boehringer Ingelheim, Debiopharm, Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, Medimmune, Takeda, Top Alliance, and OmniSeq as well as consultant fees from LOXO, X‐Biotech, Actuate Therapeutics, Roche, and NeoMed. She also serves as an advisor to Soluventis; receives speaker fees from Roche; has equity in IDbyDNA, CureMatch, and Soluventis; receives fees from Bicara Therapeutics, Biological Dynamics, Pfizer, TD2/Volastra, and Turning Point Therapeutics; serves on the boards of CureMatch and CureMetrix; and is a cofounder of CureMatch. The other authors made no disclosures. Funding Information: This work was supported by the National Cancer Institute of the National Institutes of Health (grants CA180888, CA180819, CA180821, CA233331, CA233320, and CA180828) and in part by Bristol‐Myers Squibb. The National Cancer Institute negotiated a collaborative research and development agreement with Bristol‐Myers Squibb to provide nivolumab and ipilimumab for this clinical trial. Razelle Kurzrock reports funding from the Joan and Irwin Jacobs Fund and the National Cancer Institute (grant P30 CA023100). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Sandip Pravin Patel reports that his university receives research grants from Bristol-Myers Squibb, Eli Lilly, Incyte, AstraZeneca/MedImmune, Merck, Pfizer, Roche/Genentech, Xcovery, Fate Therapeutics, Genocea, and Iovance; he also reports personal fees from Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb, Certis, Eli Lilly, Genentech, Illumina, Merck, Novartis, Pfizer, Rakuten, and Tempus. Young Kwang Chae reports research grants from AbbVie, Bristol-Myers Squibb, Biodesix, Lexent Bio, and Freenome and consulting fees, payments, and/or honoraria from Roche/Genentech, AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Counsyl, Guardant Health, Boehringer Ingelheim, Biodesix, ImmuneOncia, Lilly Oncology, Merck, Pfizer, Tempus, Lunit, and Takeda. Bhavana Konda reports research funding to her institution from Bristol-Myers Squibb, Xencor, Merck, Eisai, and Eli Lilly & Co. Elad Sharon is a full-time employee of the National Cancer Institute. Christopher W. Ryan reports clinical trial support paid to his institution from Argos, Bristol-Myers Squibb, CytRx, Daiichi-Sankyo, Exelixis, Genentech, Novartis, Karyopharm, Merck, Nektar, Pfizer, TRACON, and Xynomic and consulting fees from AstraZeneca, Bristol-Meyer Squibb, Deciphera, Exelixis, Eisai, Janssen, and Daiichi-Sanyo. Razelle Kurzrock reports research funding from Boehringer Ingelheim, Debiopharm, Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, Medimmune, Takeda, Top Alliance, and OmniSeq as well as consultant fees from LOXO, X-Biotech, Actuate Therapeutics, Roche, and NeoMed. She also serves as an advisor to Soluventis; receives speaker fees from Roche; has equity in IDbyDNA, CureMatch, and Soluventis; receives fees from Bicara Therapeutics, Biological Dynamics, Pfizer, TD2/Volastra, and Turning Point Therapeutics; serves on the boards of CureMatch and CureMetrix; and is a cofounder of CureMatch. The other authors made no disclosures. This work was supported by the National Cancer Institute of the National Institutes of Health (grants CA180888, CA180819, CA180821, CA233331, CA233320, and CA180828) and in part by Bristol-Myers Squibb. The National Cancer Institute negotiated a collaborative research and development agreement with Bristol-Myers Squibb to provide nivolumab and ipilimumab for this clinical trial. Razelle Kurzrock reports funding from the Joan and Irwin Jacobs Fund and the National Cancer Institute (grant P30 CA023100). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The trial was conducted by SWOG, and the investigational agents were provided by the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) under an NCI collaborative research and development agreement with Bristol-Myers Squibb. The protocol and all amendments were approved by SWOG, the NCI, the NCI central institutional review board, and the regulatory committees at the participating institutions. All study subjects provided their voluntary, written informed consent, and the study was conducted in accordance with the Declaration of Helsinki. Rare cancers for the S1609 cohort design were identified on the basis of an incidence of fewer than 6 in 100,000 per year.4 The cohort of high-grade neuroendocrine neoplasms was opened on the basis of ipilimumab/nivolumab activity in the aforementioned subset analysis of a neuroendocrine neoplasm cohort within S1609. Notably, this high-grade neuroendocrine cohort was distinct from and was accrued independently of previously reported neuroendocrine cohorts in S1609.3 Local pathology review was used with pathology report review by the SWOG study team. Neuroendocrine neoplasm grading was based on 2010 World Health Organization criteria; however, no separate central pathology confirmatory review was performed. Lung primary neuroendocrine neoplasms were considered eligible if the mitotic rate or Ki-67 index was >20% with the exception of small cell lung cancers, which were excluded. The pancreas as the primary site was permitted for this cohort if the tumor was high-grade. Treatment-emergent small cell neuroendocrine prostate cancer was assigned to a separate cohort of S1609 because of its unique clinical and pathologic characteristics. Microsatellite instability status, Ki-67, and primary organ site information was collected as part of the study. Patients were required to be 18 years old or older and have an Eastern Cooperative Oncology Group performance status of 0 to 2 with an absolute neutrophil count ? 1000/?L, a platelet count ? 75,000/?L, a hemoglobin level ? 8 g/dL, a creatinine clearance ? 50 mL/min, a total bilirubin level ? 2.0 ? the institutional upper limit of normal (IULN), aspartate aminotransferase and alanine aminotransferase levels ? 3.0 ? IULN, a Thyroid Stimulating Hormone or free T4 serum level ? IULN, and an adrenocorticotropic hormone level ? IULN. Women of childbearing potential were required to have a negative serum pregnancy test, and subjects were required to practice adequate birth control during protocol participation. Treatment consisted of intravenous ipilimumab (1 mg/kg) every 6 weeks with intravenous nivolumab (240 mg) every 2 weeks until disease progression, symptomatic deterioration, a treatment delay for any reason > 56 days, or unacceptable or immune-related toxicity with an inability to decrease prednisone to <10 mg daily or per patient request. Patients were evaluated with a history and a physical and toxicity assessment at least every 6 weeks at the beginning of each cycle. Laboratory evaluations included a complete blood count, a comprehensive metabolic panel, thyroid-stimulating hormone, free thyroxine, adrenocorticotropic hormone, cortisol, and lipase. Imaging studies by computed tomography for disease assessment were performed before the study; at week 8, week 16, and week 24; and then every 12 weeks until progression. The primary objective was to evaluate the ORR (confirmed complete responses and partial responses) according to version 1.1 of the Response Evaluation Criteria in Solid Tumors (RECIST) on the basis of local assessments. Publisher Copyright: © 2021 American Cancer Society
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Background: The authors previously reported the results of the nonpancreatic neuroendocrine neoplasm cohort of the SWOG S1609 DART (Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors) trial, which permitted all histologic grades and had a 44% overall response rate (ORR) among patients with high-grade disease. Here they sought to validate their findings in a dedicated prospective cohort of high-grade neuroendocrine neoplasms within S1609. Methods: A prospective, open-label, multicenter, phase 2 clinical trial of ipilimumab plus nivolumab was conducted across multiple rare tumor cohorts. The dedicated, high-grade neuroendocrine neoplasm cohort was examined here. The primary end point was the ORR according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Nineteen patients with high-grade neuroendocrine neoplasms (defined by local pathology review) were enrolled in this cohort of S1609. The most common primary sites were unknown primaries (21%), which were followed by the rectum, gastroesophageal junction, cervix, and pancreas (11%). The median number of lines of prior therapy was 1 (range, 0-3). All patients were microsatellite-stable. The median Ki-67 value was 80%. The ORR was 26% (95% confidence interval [CI], 11%-45%), and the clinical benefit rate (stable disease for ≥6 months plus partial responses plus complete responses) was 32% (95% CI, 13%-57%). The 6-month PFS rate was 32% (95% CI, 16%-61%) with a median PFS of 2.0 months (95% CI, 1.8 months to ∞) and a median OS of 8.7 months (95% CI, 6.1 months to ∞). The most common toxicities were fatigue (32%) and rash (26%), and the most common grade 3/4 immune-related adverse event was rash (15%); there were no events that required treatment discontinuation and no grade 5 events. Conclusions: Ipilimumab plus nivolumab demonstrated a 26% ORR in patients with high-grade neuroendocrine neoplasms, with durable responses seen in patients with refractory disease.
AB - Background: The authors previously reported the results of the nonpancreatic neuroendocrine neoplasm cohort of the SWOG S1609 DART (Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors) trial, which permitted all histologic grades and had a 44% overall response rate (ORR) among patients with high-grade disease. Here they sought to validate their findings in a dedicated prospective cohort of high-grade neuroendocrine neoplasms within S1609. Methods: A prospective, open-label, multicenter, phase 2 clinical trial of ipilimumab plus nivolumab was conducted across multiple rare tumor cohorts. The dedicated, high-grade neuroendocrine neoplasm cohort was examined here. The primary end point was the ORR according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Nineteen patients with high-grade neuroendocrine neoplasms (defined by local pathology review) were enrolled in this cohort of S1609. The most common primary sites were unknown primaries (21%), which were followed by the rectum, gastroesophageal junction, cervix, and pancreas (11%). The median number of lines of prior therapy was 1 (range, 0-3). All patients were microsatellite-stable. The median Ki-67 value was 80%. The ORR was 26% (95% confidence interval [CI], 11%-45%), and the clinical benefit rate (stable disease for ≥6 months plus partial responses plus complete responses) was 32% (95% CI, 13%-57%). The 6-month PFS rate was 32% (95% CI, 16%-61%) with a median PFS of 2.0 months (95% CI, 1.8 months to ∞) and a median OS of 8.7 months (95% CI, 6.1 months to ∞). The most common toxicities were fatigue (32%) and rash (26%), and the most common grade 3/4 immune-related adverse event was rash (15%); there were no events that required treatment discontinuation and no grade 5 events. Conclusions: Ipilimumab plus nivolumab demonstrated a 26% ORR in patients with high-grade neuroendocrine neoplasms, with durable responses seen in patients with refractory disease.
KW - Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART)
KW - S1609
KW - high-grade neuroendocrine neoplasms
KW - ipilimumab
KW - nivolumab
UR - http://www.scopus.com/inward/record.url?scp=85104640638&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104640638&partnerID=8YFLogxK
U2 - 10.1002/cncr.33591
DO - 10.1002/cncr.33591
M3 - Article
C2 - 33882143
AN - SCOPUS:85104640638
SN - 0008-543X
VL - 127
SP - 3194
EP - 3201
JO - Cancer
JF - Cancer
IS - 17
ER -