Biomarker testing has paved the way for immunotherapy in colorectal cancer (CRC) but perhaps not in the way that might have been predicted.
Pembrolizumab (Keytruda) and nivolumab (Opdivo) block the programmed death (PD)-1 receptor for the PD-L1 ligand, and ipilimumab (Yervoy) inhibits cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). However, all three drugs have FDA approval for CRC associated with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H). Pembrolizumab has approval for any type of tumor associated with dMMR/MSI-H, whereas the other two drugs are limited to CRC with dMMR/MSI-H.
Patients with chemotherapy-refractory CRC that is also dMMR/MSI-H can receive single-agent pembrolizumab or nivolumab or the combination of ipilimumab and nivolumab, irrespective of PD-L1 or CTLA-4 expression status. Overall, about 5% of CRCs are dMMR/MSI-H, but the rate is much higher in stage I-III disease (10%-20%) as compared with 4% in stage IV (metastatic) CRC.
Two other drugs also have tumor-agnostic approval status — entrectinib (Rozlytrek) and larotrectinib (Vitrakvi) for tumors with NTRK gene fusions. In contrast to dMMR/MSI-H, NTRK gene fusions occur in 1%-2% of CRC.
The National Comprehensive Cancer Network recommends pembrolizumab, nivolumab, or nivolumab/ipilimumab as second or third-line treatment for advanced/metastatic CRC and for patients who are not candidates for intensive therapy.
“Pembrolizumab and nivolumab appear to have similar activity as monotherapy,” said Michael Overman, MD, of the MD Anderson Cancer Center in Houston. “Cross-trial comparisons suggest that the combination of nivolumab and ipilimumab seems to produce better response rates and progression-free survival (PFS) than single-agent nivolumab or pembrolizumab. However, the combination also is more toxic, so you have to weigh that against the potential for greater effectiveness.”
Trials evaluating reduced-dose schedules suggest the nivolumab/ipilimumab toxicity can be decreased without sacrificing efficacy, he added.
The role of immunotherapy in metastatic CRC could expand in the aftermath of a practice-changing study reported during the American Society of Clinical Oncology virtual meeting. A randomized trial limited to patients with untreated metastatic dMMR/MSI-H CRC compared pembrolizumab versus standard-of-care chemotherapy with or without bevacizumab (Avastin) or cetuximab (Erbitux). The primary results showed that pembrolizumab doubled PFS and that twice as many patients in the pembrolizumab group were alive without disease progression at 24 months.
“One could argue that this was a home run for immunotherapy,” said Ryan Nipp, MD, of Massachusetts General Hospital Cancer Center in Boston. “But the results also had a very interesting wrinkle. As was pointed out during the [ASCO] discussion of the results, the PFS curves actually crossed during the first 6 months, so that the immunotherapy arm was actually doing worse. Then, as has been shown before with immunotherapy, there was a very long [survival] tail. We’ve seen it over and over again, where people who respond do really well for a long time.”
Discussion and interpretation of the findings continued among oncologists on Twitter and online forums, focusing on the early part of the survival curve.
“The point was that if you think a patient needs a quick response or is going downhill really quickly, maybe you still want to start with chemotherapy, because the chemotherapy arm was winning during the first 6 months,” said Nipp. “The thing about chemotherapy is that it gives a quicker response for patients who have bulky disease or are highly symptomatic, whereas immunotherapy often takes a few months before you see true benefits. The patient has to be well enough to get through those first few months.”
The discussion about earlier use of immunotherapy will likely continue to play out as other ongoing studies for first-line therapy reach completion, said Overman. At least one of the studies has a design to address the need for chemotherapy in certain high-risk or poor-prognosis patients. The randomized NRG-GI004/S1610 trial is comparing three regimens as initial therapy for metastatic dMMR/MSI-H CRC: the PD-L1 inhibitor atezolizumab (Tecentriq) alone, atezolizumab plus FOLFOX chemotherapy and bevacizumab, and FOLFOX plus bevacizumab.
Earlier and Earlier
Ongoing research also is evaluating strategies to enhance tumor response to immunotherapy and perhaps convert unresponsive (cold) tumors into responsive (hot) ones. Priming with chemotherapy is one possibility, but perhaps greater potential lies in the ability of radiotherapy to stimulate tumor response.
“There is a lot of interest in using chemotherapy or total body irradiation or chemoradiation to enhance response to immunotherapy,” said Suneel Kamath, MD, of the Cleveland Clinic. “Ablative radiation offers a way to destroy the tumor and possibly increase antigen production and release. I think that’s going to be a really explosive and fascinating field as time goes on.”
Although a positive dMMR/MSI-H test supports use of immunotherapy in the metastatic setting, the same is not true for patients with early-stage CRC. Most patients with stages I-III CRC do well with surgery and adjuvant chemotherapy, which might be avoided in selected low-risk patients. Testing early-stage tumors for dMMR/MSI-H status can identify patients with Lynch syndrome, which would inform decision making about treatment, genetic testing, and notification of relatives, said Overman.
Currently, none of the immune checkpoint inhibitors have approval for use in early CRC. However, the issue is under investigation. In one ongoing trial, patients with stage III dMMR/MSI-H CRC are being randomized to FOLFOX chemotherapy alone or in combination with atezolizumab. Trials evaluating neoadjuvant immunotherapy also have begun. In one small study involving patients with dMMR tumors, the combination of nivolumab and ipilimumab achieved pathologic complete response in 100% of patients.
Last Updated June 22, 2020