Single-Agent Durvalumab Elicits Responses in MSI-H CRC

Neil H. Segal, MD

The PD-L1 inhibitor durvalumab (Imfinzi) achieved objective responses in about a fourth of patients with microsatellite instability-high (MSI-H) advanced solid tumors, including colorectal cancer, 2 preliminary clinical trials showed.

Single-agent durvalumab led to objective responses in 14 of 62 patients with various types of MSI-H tumors, including 1 complete response (CR). Among 36 patients with advanced MSI-H colorectal cancer, 8 had partial responses (PRs).

In a separate single-center trial limited to MSI-H colorectal cancer, durvalumab achieved objective responses in 3 of 11 patients, including 1 CR, as reported at the 2019 Gastrointestinal Cancers Symposium.

“We’re learning that a fair number of patients with MSI-high tumors benefit from treatment with immunotherapy,” said Neil H. Segal, MD, PhD, a gastrointestinal cancer specialist and clinical director of the Immunotherapeutics Group at Memorial Sloan Kettering (MSK) Cancer Center in New York, New York. “In these studies, the benefit was consistent across different types of tumors, including colorectal cancer.”

PD-1/PD-L1 inhibitors have demonstrated clinical activity in a variety of tumors. Accumulated evidence suggests MSI-H is a marker of susceptibility to PD-1 targeted therapy. MSI-H tumors account for 3% to 4% of metastatic colorectal cancer, and recent studies found the tumors responsive to PD-1—directed therapy, Segal and colleagues noted in a poster presentation.

To examine the safety and efficacy of durvalumab in MSI-H tumors, investigators analyzed data from a phase I/II multicenter open-label trial involving patients with advanced solid tumors. Additional data came from an ongoing phase II trial at MSK, limited to patients with MSI-H colorectal cancer.

The phase I/II trial was a first-in-human study involving patients with treatment-refractory advanced solid tumors treated with 2 different doses of durvalumab. The overall study comprised 1022 patients, of whom 62 had MSI-H tumors, as determined by immunohistochemistry or polymerase chain reaction. The MSI-H subgroup had 36 patients with colorectal cancer, 17 with endometrial cancer, and 9 with other types of cancer.

Patients with stable disease (SD) or better response to therapy continued durvalumab for 12 months. Treatment beyond progression was allowed in the absence of clinical deterioration or if, in the investigator’s opinion, a patient was likely to derive benefit from continued treatment.

The primary endpoints were safety and tolerability. The key secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The MSI-H subgroup had a median follow-up of 29.16 months, and 25 of the 62 patients completed the planned 12 months of treatment with durvalumab. Of the remaining 37 patients, 27 did not complete treatment because of disease progression.

The safety analysis showed that 37 patients had at least 1 treatment-related adverse event (TRAE), including 2 grade 3/4 TRAEs. The most common TRAEs (all grades) were diarrhea (30.6%), nausea (29.0%), fatigue (24.2%), pyrexia (22.6%), back pain (22.6%), abdominal pain (21.0%), and constipation (21.0%). No patient had a fatal TRAE.

The efficacy analysis for all 62 patients showed an ORR of 22.6%. Two other patients had unconfirmed PRs. An additional 28 (45.2%) patients had SD, resulting in a DCR of almost 70%. Segal reported that 30 (48.4%) patients had disease control (response plus SD) for at least 6 months. The median DOR had yet to be reached (lower limit of the confidence interval of 12.7 months).

The efficacy analysis for the patients with colorectal cancer showed similar results. The ORR was 22.2%, 17 (47.2%) patients had SD, and 17 had disease control beyond 6 months.

The entire MSI-H cohort had a median PFS of 5.4 months (95% CI, 2.9-11.1) and a 12-month PFS of 34.7% (95% CI, 22.8-46.8). For the colorectal cancer subgroup, the median was 5.5 months (95% CI, 2.9-20.1), and the 12-month value was 37.9% (95% CI, 21.8-53.9).

Median OS was 24.2 months (95% CI, 12.4-NE), including a 12-month survival of 64.7% (95% CI, 50.7-75.6). The median survival had yet to be reached for the colorectal cancer subgroup, which had a 12-month survival of 63.3% (95% CI, 44.4-77.2).

Results of the ongoing single-center trial of patients with MSI-H colorectal cancer mirrored those of the multicenter study. Treatment with durvalumab led to an ORR of 27%, and 4 of the 11 (36.4%) patients treated thus far had SD. Five patients (45.5%) had disease control for 6 months or longer. DOR had yet to be reached.

The patients had a median PFS of 6.5 months (95% CI, 0.95-NR), and 36.3% were alive without disease progression at 12 months (95% CI, 11.2-62.7). The median OS could not yet be determined, but the 12-month survival was 79.5% (95% CI, 39.3-94.5).

Segal NH, Wainberg Z, Overman MJ, et al. Safety and clinical activity of durvalumab monotherapy in patients with microsatellite instability—high (MSI-high) tumors. J Clin Oncol. 2019;37 (suppl; abstr 670).

View more from the 2019 Gastrointestinal Cancers Symposium