Immunotherapy, Chemo Approaches Continue to Build in CRC and Pancreatic Cancer

Douglas A. Nelson, MD

Whether its immunotherapy in colorectal cancer (CRC) or chemotherapy in pancreatic cancer, a common thread among these gastrointestinal (GI) malignancies has been the investigation of these agents in earlier settings, explained Douglas A. Nelson, MD.

“I believe immunotherapy has a role in earlier lines of CRC,” he said. “In other diseases, immunotherapy started out in advanced third-line refractory settings and moved into the frontline setting, often in combination with chemotherapy. I hope that's where we're heading in CRC. There's a lot of promise in that.”

With regard to immunotherapy, data from the 2018 ESMO Congress showed a major pathologic response in 100% of patients (n = 7) with early-stage mismatch repair—deficient (dMMR) colon cancer who were treated with the combination of neoadjuvant nivolumab (Opdivo) and ipilimumab (Yervoy). Moreover, 4 patients achieved a complete response.

In the trial, 19 patients with resectable, early-stage colon cancer received 1 mg/kg of ipilimumab on day 1 and 3 mg/kg of nivolumab on days 1 and 15. Within 6 weeks of completing therapy, patients underwent surgery.

“There are a lot of exciting data coming out. There’s the evolving role of immunotherapy in multiple malignancies, including esophageal cancer, gastric cancer, and CRC, although not so much in pancreatic cancer,” said Nelson. “That's probably one of the biggest stories that’s going to continue to provide new data over the next year.”

Neoadjuvant chemotherapy could become equally as beneficial to patients with pancreatic cancer, and many investigators are now testing regimens with chemotherapy backbones in this setting. For example, data compiled from a propensity matched analysis confirmed the benefit of neoadjuvant FOLFIRINOX in patients with resectable and borderline resectable disease.

Moreover, neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine/nab-paclitaxel (Abraxane) is being tested in patients with advanced and inoperable disease, after which patients will receive stereotactic radiation in a phase I trial (NCT03600623). “I'm hoping that we'll see more data in the neoadjuvant setting emerge now that we have more effective regimens than we used to,” added Nelson.

OncLive: What compelling regimens or agents are you excited about in the CRC space?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Nelson, of the Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed key advances made in the treatment of patients with CRC and pancreatic cancer, and shed light on remaining challenges in these paradigms.Nelson: A lot of excitement came from the BEACON CRC study, which looked at the combination of an EGFR inhibitor with a BRAF inhibitor and a MEK inhibitor in patients with BRAF-mutant CRC. We're already using a similar triplet that targets BRAF, but this is a little bit different because it incorporates the MEK inhibitor without chemotherapy. The data are very encouraging so far.

We’re not quite as far along with immunotherapy in the microsatellite instability—high space. I'm looking forward to seeing some of that data in earlier lines of disease and in combination with chemotherapy, both in the advanced and adjuvant settings.

What are some remaining challenges with these patients?

Also, the idea of targeting HER2 is emerging in CRC. Although these are little slices of the pie, when you add them up, we’re talking about a significant minority of patients in whom we’re seeing really significant responses.There are patients who are not doing as well as we would like—for example, patients with right-sided tumors. These patients have a much worse survival than those with left-sided tumors.

Moving on to pancreatic cancer, what have been the most impactful studies in this setting?

Are any compelling agents coming down the pike?

How has pancreatic cancer treatment changed in recent years, and where do you see future research heading?

Additionally, patients with peritoneal carcinomatosis are a real challenge. We've had some recent negative data with hyperthermic intraperitoneal chemotherapy (HIPEC). [We’re still trying to understand] how to optimize the care for those patients and understand the role of cytoreductive surgery without HIPEC. Certainly, everyone still believe that there is a role, but [we’re still learning] how to select the appropriate patients and what we can do differently for them.We've recently seen some data with [agents] in the adjuvant setting. Certainly, the PRODIGE 24/CCTG PA.6 study with FOLFIRINOX has been a big advance, and the approach has been adopted as a standard for patients who can handle that therapy. Now, we're looking to see how those data turn out with the alternative regimen of gemcitabine and nab-paclitaxel. We’re also looking at [those regimens] in both the neoadjuvant and adjuvant settings.We’re looking at agents that can interrupt the extracellular matrix with regard to specific subsets of patients—specifically, those with high levels of hyaluronic acid. Agents that can target stem cells is another approach. These are promising avenues of investigation, but we're still waiting for data.There has been increasing interest in the neoadjuvant setting. Defining the role of radiation still remains of interest; we want to determine whether this approach has a role, and, if so, whether it should be used in combination with chemotherapy or [alone as] stereotactic radiotherapy.

Chalabi M, Fanchi LF, Van den Berg JG, et al. Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Ann Oncol. 2018;29(suppl 8; abstr LBA37_PR.). doi: 10.1093/annonc/mdy424.047.