Immunotherapy Combo Is Promising in MSI-H Colorectal Cancer


The frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed a robust and durable clinical benefit in patients with metastatic colorectal cancer (mCRC) whose tumors are microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR)—a population with a historically poor prognosis, said Heinz-Josef Lenz, MD, FACP.

The frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed a robust and durable clinical benefit in patients with metastatic colorectal cancer (mCRC) whose tumors are microsatellite instability—high (MSI-H)/mismatch repair deficient (dMMR)—a population with a historically poor prognosis, said Heinz-Josef Lenz, MD, FACP.

In the phase II CheckMate-142 trial, investigators examined the safety and efficacy of nivolumab plus low-dose ipilimumab as first-line treatment in treatment-naïve patients with MSI-H/dMMR mCRC (n = 45). Results that were previously presented at the 2018 ESMO Congress showed an overall response rate (ORR) of 60% and a disease control rate of 84% in 45 patients.1 Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) had not been reached.

At the 2019 ASCO Annual Meeting, Lenz, professor of medicine, J. Terrance Lanni Chair in Gastrointestinal Cancer Research, and co-director, University of Southern California (USC) Center for Molecular Pathway and Drug Discovery, at the USC Norris Comprehensive Cancer Center, presented a clinical update on the trial. At a median duration of follow-up of 19.9 months, the investigator-assessed ORR with the combination increased to 64% (95% CI, 49-78) per investigator assessment, and 84% of patients (95% CI, 71-94) had disease control for ≥12 weeks.2The median DOR, PFS, and OS had still not been reached.

Previously, in July 2018, the FDA granted an accelerated approval to this immunotherapy combination for the treatment of adult and pediatric patients 12 years and older with MSI-H or dMMR mCRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

In an interview with OncLive, a sister publication of Oncology Nursing News, Lenz highlighted the advances made with immunotherapy in mCRC, updates of the CheckMate-142 trial, and where future research should be focused in order to further improve patient outcomes.

OncLive: What progress has been made with immunotherapy in mCRC?

Lenz: We have come a long way with integrating immunotherapy into the treatment of [patients with] CRC. We have figured out that MSI-H tumors are very sensitive to immune checkpoint blockade. Data highlighted in the New England Journal of Medicine have clearly shown that mismatch repair-deficient tumors are significantly [responsive] to PD-1 blockade in the refractory setting. This has been seen with pembrolizumab (Keytruda) as well as with nivolumab.

Could you expand on the headway made in those with MSI-high/dMMR disease?

After the initial data [seen] in the refractory setting with response rates over 50%, the big question is, “Do we even need chemotherapy in this patient population?” [Those data] actually led to the testing of immune blockade, either PD-1 alone or in combination with CTLA-4 inhibition, in the frontline [setting]. There are several ongoing clinical trials, either examining immunotherapy alone or in combination with chemotherapy. The question is, “Even in this patient population, can the efficacy further be [improved] by combining [immunotherapy] with chemotherapy or a targeted agent?”

Could you provide some background on the CheckMate-142 trial and the data we have seen thus far with nivolumab/ipilimumab?

The phase II single-arm study of the combination of nivolumab and ipilimumab [in the frontline setting] was presented at the 2018 ESMO Congress and it showed, for the first time, very high efficacy in a patient population—those with MSI-H tumors, which are usually right-sided tumors, and one-third of these patients have BRAF mutations—that prognostically perform very poorly. However, the response rate was over 55%. PFS was not reached, OS was not reached, and neither was DOR, indicating a very highly effective treatment regimen for patients who never have seen chemotherapy at the time of diagnosis.

At the 2019 ASCO Annual Meeting, we have an update. The median follow-up in the presentation given in Munich was only 9 months; now it's 20 months. [We have shown] that the response rate further increased to 64% and we still have not reached PFS or OS, indicating that this combination is highly effective in the first-line setting.

In the future, there will be a challenging question we will need to address for patients with MSI-H disease: “Do they really need to experience cytotoxic chemotherapy treatment or can they be treated with first-line immunotherapy?” Whether a combination composed of immunotherapy and chemotherapy further increases benefit needs to be shown, but it is unclear in the presence of this very highly effective treatment.

One of the biggest limitations is that it is a very small, single-arm study; is this enough to move [this regimen] upfront? I believe the regulatory agencies need to review these [data]. There is an ongoing trial we are waiting for that is looking at pembrolizumab alone versus in combination with chemotherapy [in this space]. I believe that would further solidify the potential benefit of first-line immunotherapy in this patient population.

Were there any new safety signals reported?

That’s a very important question. The [dosing with this] combination is different than other ipilimumab/nivolumab combinations [that have been investigated]. When ipilimumab was given at 1 mg every 6 weeks, there were no additional adverse events compared with when nivolumab is given alone. In the past, higher doses of ipilimumab and more frequent administration led to significant gastrointestinal toxicities. [By changing the] schedule and the dose, that [challenge] has completely disappeared. We are very comfortable that this treatment is very well tolerated and has incredible efficacy.

Could you expand on the clinical implications of this research?

What is interesting with the data is that the response rate went up, the 1-year OS rate went up, and the PFS is still not reached, indicating the data are extremely immature right now for survival. It will be at least longer than 14 or 15 months for PFS; as such, this will be superior to any other treatment options. Considering that these patients have a median survival of 22 or 23 months with chemotherapy, to have a 1-year survival of over 84% is amazing, and the DOR has not been reached. The patients who benefit, really benefit for a long, long time.

What unanswered questions need to be addressed with future research?

With regard to microsatellite instability, we still do not know about the 10% of patients with innate resistance. Who are these patients, and can we include them in this incredible efficacy profile? Those questions remain.

Also, the biggest elephant in the room is, what do we do with the patients who do not have MSI-H tumors? How can we make them benefit from immune checkpoint blockade? To this end, at the 2019 ASCO Annual Meeting, there was an incredibly impressive abstract from Japan that looked at combining regorafenib (Stivarga) with nivolumab in patients with microsatellite stable (MSS) disease. About 53 patients were treated with [the combination and had] a response rate of 40%. This is unheard of in the refractory population.

There are ongoing data showing that anti-VEGF treatment may be synergistic with PD-1 blockade. Now, for the first time in an MSS population, we are seeing very impressive efficacy by combining these 2 treatment strategies. Therefore, I'm very optimistic that there will be many more [options] coming [down the pike] for patients with MSS disease by combining anti-VEGF strategies with immune checkpoint inhibition.

Read more: Metastatic Colorectal Cancer Treatments Continue to Change

This article originally appeared on OncLive as, "Frontline Nivolumab/Ipilimumab Combo Shows Robust Activity in MSI-H/dMMR mCRC."

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