CheckMate-142 is a nonrandomized, multi-arm, phase II study designed to determine whether nivolumab alone or in combination with other anticancer drugs can yield meaningful reductions in tumor size in patients with colorectal cancer (CRC) that has metastasized or recurred following at least one prior line of therapy. Importantly, the trial is specifically focused on patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) disease.
Although only about 4% of patients with stage II CRC have a deficiency in the dMMR system that leads to MSI-H disease, these patients pose a considerable challenge in the clinic because their disease demonstrates a low likelihood of response to conventional chemotherapy. Researchers hypothesized that the wealth of neoantigens produced in these genetically unstable tumors could potentially be exploited by immunotherapies, such as nivolumab and ipilimumab, which unleash the power of the adaptive immune system. This concept is now being borne out by CheckMate-142 findings.
Evaluation of Nivolumab and Ipilimumab in Combination
Dr. Thierry André presents Abstract 553 during Oral Abstract Session C.
“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,” commented Thierry André, MD, of the Saint-Antoine Hospital, in France.
The nivolumab/ipilimumab findings build on the CheckMate-142 results already published showing that nivolumab monotherapy conferred durable responses, sustained disease control, and prolonged survival in previously treated patients with dMMR/MSI-H mCRC. Since nivolumab and ipilimumab inhibit two different immune checkpoints that restrain the adaptive immune response—the PD-1/PD-L1 checkpoint and the CTLA-4 checkpoint, respectively1—the hope was that combining them would enhance the response to treatment. Indeed, the ORR with nivolumab monotherapy reached 31% but, as noted above, it increased to 55% with the addition of nivolumab when the rates for the two regimens at 13.4 months of follow-up were compared.
The combination immunotherapy regimen consisted of four doses of nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks, followed by administration of nivolumab 3 mg/kg every 2 weeks. ORR per investigator assessment was the primary endpoint of interest.
The 119-patient cohort comprising the nivolumab/ipilimumab arm had a median age of 58 years, 59% were male, and 55% had an Eastern Cooperative Oncology Group performance status of 1 (the highest allowed). Forty-five percent of patients had stage IV CRC at diagnosis, and 29% had a known history of Lynch syndrome. Mutations in BRAF (24%) and KRAS (37%) were identified in more than half of patients, and 22% of patients had high PD-L1 expression (i.e., ≥ 1%) on tumor cells at baseline.
The cohort was treatment-experienced, with 23%, 36%, and 40% having received one, two, and three or more prior lines of therapy, respectively.
The 55% ORR (95% CI [45.2%, 63.8%]) observed for the entire cohort largely consisted of partial responses (51.3%) with a few complete responses (3.4%). Seventy-eight percent of patients showed some degree of reduction in tumor burden from baseline, even though not all met the definition of clinical response.
The median time to response was 2.8 months (range 1 to 14 months), and the median duration of response has not yet been reached. Among the patients who responded to treatment, 94% had ongoing responses at the time of data cutoff. At the time of this report, 63% of patients in the nivolumab/ipilimumab cohort remained on treatment.
Responses were observed regardless of tumor PD-L1 expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome. Across all patient subsets for these factors, the ORR ranged from 48% to 71% and the DCR ranged from 77% to 86%.
Combined treatment with nivolumab and ipilimumab also provided sustained benefits in progression-free survival (PFS) and overall survival (OS), with improvements over results for nivolumab alone. The 1-year PFS rate and 1-year OS rate with the combination regimen were 71% and 85%, respectively.
Dr. André reported that patients who received nivolumab plus ipilimumab achieved statistically significant and clinically meaningful improvements in quality-of-life measures that were maintained for extended periods while patients remained on treatment. “In my experience, this is the first time I have had a very large number of patients going back to work in this very advanced disease,” he said.
No new safety signals emerged with the addition of ipilimumab to nivolumab. A comparison of safety between combination therapy and nivolumab monotherapy revealed similar rates of all-grade treatment-related adverse events (73% and 70%, respectively) and a modest increase in the rate of grade 3/4 treatment-related adverse events (32% and 20%, respectively). Treatment-related adverse events leading to study drug discontinuation were also more common with combination therapy than monotherapy (13% and 7%, respectively). The most common events overall were diarrhea (22%), fatigue (18%), pruritus (17%), and pyrexia (15%).
Discussant Zsofia Kinga Stadler, MD, of Memorial Sloan-Kettering Cancer Center, found the nivolumab/ipilimumab results very encouraging, but she qualified their clinical significance. “It is unclear if combination immunotherapy provides long-term clinical benefit over anti–PD-1 monotherapy,” she said.
Determining this will require large randomized comparisons of monotherapy versus combination therapy, as has been done in melanoma.
“Even then, cost and value become important factors in the decision of who to select for combined therapy,” Dr. Stadler said.
Dr. Michael Overman presents Abstract 554 during Oral Abstract Session C.
Longer Follow-Up of Nivolumab Monotherapy
Published results from CheckMate-142 previously established that nivolumab monotherapy provides meaningful clinical benefit to patients with dMMR/MSI-H mCRC. Following 13 months of follow-up, the ORR was 32% per blinded independent central review (BICR) and 73% of patients remained alive at 1 year.
The U.S. Food and Drug Administration granted accelerated approval to nivolumab for the subset of patients with disease progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy, owing to the BICR ORR of 28%.
Michael J. Overman, MD, of the University of Texas MD Anderson Cancer Center, presented longer follow-up results for the nivolumab monotherapy cohort and subgroups within this cohort. They key subgroups of interest included 53 patients who received three or more prior chemotherapies, including a fluoropyrimidine, oxaliplatin, and irinotecan, and the 21 patients who had not yet received treatment with all three of these chemotherapies.
Based on a median follow-up duration of 21 months, the ORR per BICR in the nivolumab monotherapy cohort was 34%—26% for fluoropyrimidine, oxaliplatin, and irinotecan–experienced patients and 52% for patients who had not yet received all three of these agents. The median duration of response had still not yet been reached in the overall cohort or the two subgroups. Among responders, 80% had ongoing responses at the time of data cutoff, and 64% had responses lasting 1 year or more.
The complete response rate deepened with longer follow-up. Whereas only 3% of patients had attained a complete response to nivolumab monotherapy after a median of 13 months, 9% had done so after a median of 21 months.
Median PFS for the overall cohort reached 6.6 months (95% CI 3.0-not estimable). However, as Dr. Overman noted, “that does not well represent the benefit from this therapy. A better representation is that at 12 months, we see a PFS rate of 44%, which at 18 months is exactly the same at 44%.”
Median OS has not been reached. OS rates at 12 and 18 months were 72% and 67%, respectively, also showing strong durability. Minimal difference in 18-month OS rates was found for patients who had received fluoropyrimidine, oxaliplatin, and irinotecan and those who had not (66% and 70%, respectively).
No new safety signals emerged with long-term follow-up. Twenty percent of patients experienced grade 3/4 treatment-related adverse events, the most common being increased lipase (8%).
“Longer-term follow-up continues to support the use of nivolumab monotherapy in previously treated dMMR/MSI-H CRC. The extremely impressive disease control rate and the increased complete response to 9% is reassuring,” Dr. Stadler commented.
Several provocative questions were raised about the CheckMate-142 findings. First, clinicians sought guidance on how long nivolumab or nivolumab/ipilimumab should be continued in patients with dMMR/MSI-H CRC before ceasing treatment. Second, in an effort to treat as conservatively as possible, several questions pertained to sequencing, step-up, and/or step-down approaches with nivolumab and ipilimumab based on a patient’s response to treatment. These questions remain to be addressed.
Read more in the Journal of Clinical Oncology.
– Kara Nyberg, PhD