SAN FRANCISCO — There are now more data to support the use of nivolumab (Opdivo, Bristol-Meyers Squibb) as a treatment for DNA mismatch repair-deficient (dMMR)/microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC), either as a monotherapy or in combination.
The supporting evidence comes from two studies from the CheckMate-142 trial. That trial was the basis of the US Food and Drug Administration’s (FDA’s) granting accelerated approval to nivolumab for this indication last year.
One study provides an update regarding nivolumab monotherapy. It showed that the clinically meaningful and durable responses continued with longer-term use within the cohort. There was also a deepening of responses with longer follow-up. Between the first median follow-up at 13 months and the second at 21 months, five additional patients achieved a complete response.
The second study, which evaluated the combination of nivolumab and ipilimumab (Yervoy, Bristo-Meyers Squibb), found that the combination also produced durable clinical responses during a median follow-up of 13 months. An overall response rate (ORR) of 55% was reported; the median duration of response was not reached.
Abstracts of both studies were presented here at the Gastrointestinal Cancers Symposium (GICS) 2018.
Nivolumab as Monotherapy
CheckMate-142 is a nonrandomized, multiarm, phase 2 study that was designed to evaluate the use of nivolumab alone or in combination with ipilimumab in the treatment of dMMR/MSI-H mCRC.
“With 13 months of follow-up, the overall response rate was 32% per blinded independent central review, and 73% of patients were alive at 1 year,” said lead author Michael J. Overman, MD, assistant professor, Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, referring to the earlier findings. “These results provided the rationale for extending the follow-up.”
The FDA approval was based on outcomes observed in the subset of patients who had experienced disease progression during or after chemotherapy regimens containing fluoropyrimidine, oxaliplatin, and irinotecan.
The cohort included 74 patients with dMMR/MSI-H mCRC who received nivolumab 3 mg/kg every 2 weeks. The patients were followed for up to 21 months. An exploratory analysis assessed treatment efficacy in light of previous chemotherapy. Group A (n = 53) included patients previously treated with three or more prior chemotherapy regimens (fluoropyrimidine, oxaliplatin, and irinotecan). Group B (n = 21) comprised patients who had not been treated with all three of these regimens.
The ORR was 34%; not surprisingly, a higher response rate was observed in group B vs group A (52% vs 26%). Among patients who experienced a response, those responses were ongoing in 80% of patients at the time of data cutoff; 64% achieved responses of 1 year or longer in duration.
The median duration of response has not been reached in the overall cohort or either subgroup. The median time to response was about 2.8 months for all patients.
The complete response rate deepened with longer follow-up, Dr Overman noted. At 13 months, only 3% of patients had achieved a complete response, but that number grew to 9% (n = 7) at a median of 21 months.
A partial response was achieved in 24% (n = 18), and stable disease was achieved in 31% (n = 23); 30% (n = 22) had progressive disease. The disease control rate extrapolated to 62%.
For patients in group B, the complete response rate was higher as compared with group A (14% vs 8%), as was the partial response rate (38% vs 19%) and the stable disease rate (33% vs 30%).
The median progression-free survival was 6.6 months; it was lower for group A (4.2 months) and was not reached in group B. But those data do not completely represent the benefit from this therapy, said Dr Overman. “A better representation is that at 12 months, we see a progression-free survival rate of 44%, which at 18 months is exactly the same at 44%.”
Median overall survival has not been reached but was 72% at 12 months and 67% at 18 months. For groups A and B, 12-month overall survival was 68% and 81%, respectively; at 18-months, overall survival was 66% and 70%, respectively.
“Patients with a best overall response of progressive disease who had a reduction in or stabilization of target lesions were more likely to survive 12 months,” said Dr Overman.
There were no new safety signals with longer-term follow-up, and 20% of the cohort experienced grade 3/4 treatment-related adverse events.
Two Immunotherapies
In the second study, 119 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab every 2 weeks. The median follow-up was 13.4 months.
The median progression-free and overall survival rates were not reached; 85% of patients remained alive at 1 year.
“Indirect comparisons in CheckMate-142 suggest that nivolumab plus ipilimumab provides numerically higher response rates and improved long-term clinical benefit relative to nivolumab monotherapy in this nonrandomized trial,” said lead author Thierry André, MD, of the Saint-Antoine Hospital, Paris, France.
This trial builds on the findings from the monotherapy arm of CheckMate-142 in that nivolumab has already demonstrated durable responses, sustained disease control, and encouraging survival in patients with dMMR/MSI-H mCRC.
“The rationale to combine nivolumab and ipilimumab is that they act synergistically to promote T-cell antitumor activity; therefore, combination therapy could further improve results,” Dr André said.
Similar to the monotherapy group, patients in this cohort were heavily pretreated, with 76% having received two or more prior lines of therapy. Nearly all had received fluoropyrimidine (99%) and oxaliplatin (93%), and roughly three quarters had received irinotecan (73%).
At the data cutoff, 75 (63%) patients were continuing treatment. The primary reason for stopping therapy was disease progression (n = 23, 19%), followed by adverse events related to study drugs (n = 16, 13%). Among patients who responded, those responses were ongoing for 94% at data cutoff.
The overall response rate was 55%, with 51% experiencing stable disease; 51.3%, partial response; and 3.4%, a complete response. The majority of patients (78%) experienced some degree of tumor reduction from baseline.
The disease control rate was 80% with combination therapy.
“This compares favorably with the monotherapy group, which had an overall response rate of 34%, a stable disease rate of 38%, and a disease control rate of 69%,” said Dr André.
The 9- and 12-month rates of progression-free survival were 76% and 71%, which were more favorable than were seen with nivolumab monotherapy (54% and 50%). Similarly, overall survival at 9 and 12 months was also superior (87% and 85%) in comparisoin with nivolumab alone (78% and 73%).
“Most impressive were the Kaplan-Meier curves for progression-free and overall survival,” emphasized Dr André.
The authors also assessed quality of life using the EORTC QLQ-C30 global health status/QoL and the EQ-5D visual analogue scale. Patients achieved statistically significant and clinically meaningful improvements that were maintained for extended periods.
“Nivolumab plus ipilimumab represents a promising new treatment option for patients with previously treated dMMR/MSI-H mCRC,” concluded Dr André.
No new safety signals were observed in this cohort. Grade 3/4 treatment-related adverse events occurred in 32% of patients; 13% experienced events of any grade; and 10% discontinued treatment because of adverse events. There were no treatment-related deaths.
Two Better Than One?
In a discussion of the two abstracts, Zsofia K. Stadler, MD, associate attending physician at Memorial Sloan Kettering Cancer Center in New York City, noted that longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR/MSI-H CRC.
“A clinical benefit is seen regardless of prior chemotherapy with a fluoropyrimidine, oxaliplatin, and irinotecan,” said Dr Stadler. “Evaluation of anti-PD1 therapies in the first-line setting is warranted.”
For the combination therapy, Dr Stadler pointed out that “there is insufficient evidence that combination therapy is superior to monotherapy with anti-PD-1, and the two studies are not intended for comparison or to show superiority.”
She noted that survival data are not mature and that follow-up is short.
“It is unclear if combinations of immunotherapy provides long-term clinical benefit over anti-PD-1 monotherapy — and this will require randomized comparisons of monotherapy vs combination therapy,” Dr Stadler added.
The CheckMate-142 was funded by Bristo-Meyers Squibb. Dr André has served in a consulting or advisory role with Roche/Genentech, Amgen, Bristol-Myers Squibb, Mundipharma, HalioDX, MSD Oncology, and SERVIER. He has received travel, accommodations, and other expenses from Roche/Genentech, Amgen, and Bristol-Myers Squibb; and honoraria from Roche/Genentech, Sanofi, Lilly, Baxter, Bayer, Bristol-Myers Squibb, MSD Oncology, Boehringer Ingelheim, Celgene, SERVIER, Xbiotech, and Novartis. Dr Overman has served in a consulting or advisory role with Bristol-Myers Squibb, Merrimack, and Roche/Genentech and has received research funding from Amgen, Bristol-Myers Squibb, Celgene, MedImmune, Merck, and Roche.
Gastrointestinal Cancers Symposium (GICS) 2018. Abstracts 553 and 554, presented January 20, 2018.
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