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Clinical Trial
. 2020 May 15;26(10):2290-2296.
doi: 10.1158/1078-0432.CCR-19-3356. Epub 2020 Jan 22.

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors

Sandip P Patel #  1 , Megan Othus  2 , Young Kwang Chae #  3 , Francis J Giles  4   5 , Donna E Hansel  6 , Preet Paul Singh  7 , Annette Fontaine  8 , Manisha H Shah  9 , Anup Kasi  10 , Tareq Al Baghdadi  11 , Marc Matrana  12 , Zoran Gatalica  13 , W Michael Korn  13   14 , Jourdain Hayward  15 , Christine McLeod  15 , Helen X Chen  16 , Elad Sharon  16 , Edward Mayerson  2 , Christopher W Ryan  17 , Melissa Plets  2 , Charles D Blanke  18 , Razelle Kurzrock  1
Affiliations
Clinical Trial

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors

Sandip P Patel et al. Clin Cancer Res. .

Abstract

Purpose: Immune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).

Patients and methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.

Results: Thirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.

Conclusions: Ipilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease.

Trial registration: ClinicalTrials.gov NCT02834013.

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Figures

Figure 1.
Figure 1.. Waterfall and Swimmer’s plots of tumor measurements.
Gray lines at −30% and 20% indicate lines for partial response and progression per RECIST 1.1, respectively. Asterisk (*) and hatched bars in waterfall plots indicate patients who had early clinical progression (N = 3) or new lesions without assessable RECIST changes (N = 5; includes one patient who had new lesions on day 59, but currently remains on study with clinical benefit 326+ days after treatment initiation with confirmed iPR); these patients are shown as 21% increase indicating progression. A) Overall waterfall plot; B) Waterfall plot by primary site; C) Waterfall plot by tumor grade; D) Swimmer’s plot by tumor grade
Figure 1.
Figure 1.. Waterfall and Swimmer’s plots of tumor measurements.
Gray lines at −30% and 20% indicate lines for partial response and progression per RECIST 1.1, respectively. Asterisk (*) and hatched bars in waterfall plots indicate patients who had early clinical progression (N = 3) or new lesions without assessable RECIST changes (N = 5; includes one patient who had new lesions on day 59, but currently remains on study with clinical benefit 326+ days after treatment initiation with confirmed iPR); these patients are shown as 21% increase indicating progression. A) Overall waterfall plot; B) Waterfall plot by primary site; C) Waterfall plot by tumor grade; D) Swimmer’s plot by tumor grade
Figure 1.
Figure 1.. Waterfall and Swimmer’s plots of tumor measurements.
Gray lines at −30% and 20% indicate lines for partial response and progression per RECIST 1.1, respectively. Asterisk (*) and hatched bars in waterfall plots indicate patients who had early clinical progression (N = 3) or new lesions without assessable RECIST changes (N = 5; includes one patient who had new lesions on day 59, but currently remains on study with clinical benefit 326+ days after treatment initiation with confirmed iPR); these patients are shown as 21% increase indicating progression. A) Overall waterfall plot; B) Waterfall plot by primary site; C) Waterfall plot by tumor grade; D) Swimmer’s plot by tumor grade
Figure 1.
Figure 1.. Waterfall and Swimmer’s plots of tumor measurements.
Gray lines at −30% and 20% indicate lines for partial response and progression per RECIST 1.1, respectively. Asterisk (*) and hatched bars in waterfall plots indicate patients who had early clinical progression (N = 3) or new lesions without assessable RECIST changes (N = 5; includes one patient who had new lesions on day 59, but currently remains on study with clinical benefit 326+ days after treatment initiation with confirmed iPR); these patients are shown as 21% increase indicating progression. A) Overall waterfall plot; B) Waterfall plot by primary site; C) Waterfall plot by tumor grade; D) Swimmer’s plot by tumor grade
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