Immunotherapy Advancements Making Strides in GI Malignancies

The introduction and integration of immunotherapy in the neoadjuvant setting for gastrointestinal malignancies represents a shifting paradigm, Andrea Cercek, MD, head of the Colorectal Cancer Section and codirector of the Center for Young-Onset Colorectal and Gastrointestinal (GI) Cancers, Memorial Sloan Kettering Cancer Center, said during her keynote talk at an Institute for Value-Based Medicine® (IVBM) event cohosted by The American Journal of Managed Care and UPMC Hillman Cancer Center.

The full-day IVBM event was cochaired by Anwaar Saeed, MD, UPMC Hillman Cancer Center, and Amer Zureikat, MD, FACS, University of Pittsburgh Medical Center. The day provided insights into the latest advancements and updates in treatment broken out into 4 main sessions, each with multiple presentations: esophageal and gastric cancers, pancreatic and neuroendocrine cancers, hepatobiliary cancer, and colorectal cancer. In addition to multiple presentations, each session was capped with a panel discussion.

Speakers at the event were affiliated with a variety of cancer centers and organizations, including Houston Methodist Neal Cancer Center, Memorial Sloan Kettering Cancer Center, Moffitt Cancer Center, Novant Health, University of Pittsburgh Medical Center, and more.

Cercek’s keynote took place in the middle of the event. She noted that progress in the utilization of immunotherapy in the neoadjuvant space for GI cancers really applies to locally advanced microsatellite instability (MSI) or deficient mismatch repair (dMMR) tumors, which represents about 15% of colon cancers and 5% to 10% of rectal cancers.

“We know these tumors are a lot less sensitive to chemotherapy,” Cercek said. “We learned that in the adjuvant setting.” Research has shown this in the neoadjuvant setting as well, she added. These tumors are also associated with Lynch syndrome, which makes it important to do germline testing in these tumors.

The standard treatment in rectal cancers is a combination of chemotherapy, radiation, and surgery. Patients frequently achieve a cure, but radiation and surgery have life-altering consequences.

“The idea is, in rectal cancer in general, to try to optimize neoadjuvant therapy to minimize at least surgery and look to nonoperative management, but to potentially also omit radiation,” she said.

The early thought in dMMR rectal cancer was to use PD-1 blockade to replace chemotherapy, replace chemotherapy and radiation, or even to replace chemotherapy, radiation, and surgery. A study of dostarlimab was designed to test this hypothesis.¹ In the study, patients would receive dostarlimab every 3 weeks for 6 months, then undergo radiologic and endoscopic evaluation. If they had no tumor, they would be followed up every 4 months with no further therapy and nonoperative management. If they had residual disease, they would receive chemotherapy and radiation therapy and were evaluated again. Patients who still had residual disease would progress to surgery.

The target enrollment had been 30 patients with stage II and III dMMR rectal cancer. However, they’ve expanded the trial, and it is ongoing. A total of 36 patients were enrolled as of March 2023 with a median age of 50 years. The majority (94%) were node positive with large tumors (T2 staging, 47%; T4 staging, 25%), which would have made chemoradiation and surgery likely.

The study met both primary end points of overall response rate of PD-1 blockade with or without chemoradiation and pathologic complete response (pCR) or clinical complete response rate at 12 months after PD-1 blockade with or without chemoradiation.

All 23 patients who completed the dostarlimab treatment had a complete response without needing radiation or surgery. On follow-up there was no recurrence, local regrowth, or distant metastatic disease. Most patients needed 6 months to achieve a clinical complete response, but there were some who reached this milestone at 3 months.

“We believe this highlights the importance of biomarker-
directed therapy,” Cercek said. Since publishing the data from this study, neoadjuvant PD-1 therapy has been incorporated into the National Comprehensive Cancer Network (NCCN) guidelines for dMMR locally advanced rectal cancer.²

Neoadjuvant therapy in colon cancer was first explored in the NICHE study out of the Netherlands (NCT03026140).³ The study looked at 30 patients with dMMR and 30 with proficient mismatch repair (pMMR) tumors. The patients had resectable, previously untreated adenocarcinoma of the colon and in the study, they received 1 month of nivolumab and ipilimumab followed by surgery within 6 weeks.

There was an early response for these patients with 69% pCR, and 97% had a major response.

NICHE-2 was a larger study of the same design with 112 patients with no major significant toxicities.⁴ The pCR was 67%, “which is really exciting,” Cercek said. The long-term follow-up with disease-free survival data is expected sometime in 2024.

In addition, 99% of patients had more than a 50% pathologic response and 95% had a major pathologic response.

Other studies in colon cancer have shown similar results with significant tumor regression and 67% to 75% pCR rates. “We’re left wondering a little bit, how much treatment is needed,” Cercek said. In studies, duration of treatment can vary from 1 to 6 months and treatment could be single agent or doublet, she noted. “You do wonder with these responses with single agent if a doublet is really necessary. The counterargument is that with the single agent you appear to need longer treatment.”

In rectal cancer, utilization of neoadjuvant immunotherapy has “changed the treatment paradigm,” Cercek said. Patients can avoid chemotherapy, radiation therapy, or surgery, which is a departure from the prior standard of care.

Despite the “phenomenal” responses in colon cancer, these patients all had to go on to surgery, she said. “Assessment of a clinical complete response is quite challenging in colon cancer.” In the metastatic setting, resected lesions resulted in a pCR up to 60% of the time. “It’s scarred, it’s not active disease, but for all intents and purposes, it looks like viable tumor. So that’s a challenge,” Cercek explained.

There are also data in the gastric cancer space regarding the use of neoadjuvant immunotherapy. In the GERCOR NEONIPIGA study,⁵ 32 patients with dMMR microsatellite instability-high (MSI-H) gastric tumors were treated with neoadjuvant nivolumab plus ipilimumab. A pCR was reported in 59% of patients and at a median follow-up of 10.9 months, 94% of patients were recurrence/progression-free. “That’s a huge gain in gastric cancer and in this approach in the neoadjuvant setting,” Cercek said.

This is another area where NCCN guidelines have been updated to include neoadjuvant immunotherapy for MSI-H gastric cancer.⁶

The goal should be to shift definitive therapy to just immunotherapy and avoid surgery, Cercek said, but there remains work to be done with this treatment approach to feel confident the tumor is gone. “That’s a bit of an open area still that requires further research in gastric cancer,” she said, but there are ongoing studies looking to address this. 

References

1. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445
2. NCCN. Clinical Practice Guidelines in Oncology. Rectal cancer, version 6.2023. Accessed November 22, 2023. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf.
3. Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566-576. doi:10.1038/s41591-020-0805-8
4. Chalabi M, Verschoor YL, van den Berg J, et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: the NICHE-2 study. Ann Oncol. 2022;33(suppl 7):S1389. doi:10.1016/j.annonc.2022.08.016
5. André T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): the GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022;40(suppl 4):244. doi:10.1200/JCO.2022.40.4_suppl.244
6. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 2.2023. Accessed November 22, 2023. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf