Research in mCRC Underscores Importance of Individualized Approach

Michael J. Overman, MD

Key elements that should inform treatment decisions for patients with metastatic colorectal cancer (mCRC) include molecular profiling, tumor sidedness, and microsatellite instability—high (MSI-H)/mismatch repair deficient (dMMR) status, according to Michael J. Overman, MD.

“Molecular testing is key. We have to test all of our patients in the frontline setting for these critical markers that we can act on. There are data out there to suggest that we're not doing this, and we're harming our patients by not doing this,” stressed Overman. “The subsets [of patients with these alterations] are rare, but as you look at the various subsets, they add up. We’re also starting to talk about a good number of patients with mCRC who may have BRAF V600E mutations, HER2 amplification, or have MSI-H/dMMR tumors. These are all areas for which we have great new therapies.”

Updated results from the phase III BEACON CRC trial showed that patients with BRAF V600E—mutant mCRC who received 1 or 2 prior lines of therapy experienced a median overall survival (OS) of 9.3 months with the BRAF inhibitor encorafenib (Braftovi) plus cetuximab (Erbitux).¹ Previously reported data of the doublet plus binimetinib (Mektovi) showed a median OS of 9.0 months versus 5.4 months in the control arm, which was comprised of investigator’s choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (HR, 0.52; 95% CI, 0.39-0.70; P <.001).²

In August 2018, the triplet was granted a breakthrough therapy designation by the FDA in this indication. In December 2019, the FDA granted a priority review designation to a supplemental new drug application for the doublet for the treatment of this patient population.

For patients with MSI-H tumors, immunotherapy has garnered significant interest, particularly in the frontline setting. While immunotherapy is approved for use in this patient population following progression on a fluoropyrimidine, oxaliplatin, and irinotecan, updated results from the phase II CheckMate-142 study showed a continued progression-free survival (PFS) benefit with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with MSI-H/dMMR tumors, suggesting that checkpoint inhibitors could also play a role in the frontline setting.³

Larger trials, such as the phase III KEYNOTE-177 (NCT02563002) and SWOG S1610 (NCT02997228) trials, are also underway. The former is evaluating pembrolizumab (Keytruda) monotherapy in patients with MSI-H or dMMR stage IV CRC, and the latter is examining the use of chemotherapy and bevacizumab (Avastin) with or without atezolizumab (Tecentriq) in those with dMMR mCRC.

While data with immunotherapy have been less robust in the microsatellite stable (MSS) population, results of a small phase Ib trial presented at the 2020 Gastrointestinal Cancers Symposium showed that the combination of regorafenib (Stivarga) and nivolumab led to an objective response rate of 29% in this population.⁴

In later lines of therapy, regorafenib and TAS-102 (trifluridine/tipiracil; Lonsurf) can be used, according to Overman. While the toxicity profile of regorafenib was a concern in the past, results of the phase II ReDOS trial showed similar outcomes with standard dosing and a dose-escalated approach.⁵

In an interview during the 2020 OncLive^® State of the Science Summit^™ on Gastrointestinal Malignancies, Overman, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine and committee vice chair at The University of Texas MD Anderson Cancer Center, discussed the current treatment landscape of mCRC and ongoing research efforts in the space.

OncLive: What molecular markers should be tested for in mCRC?

Overman: [The discovery of] molecular subtypes has changed how we practice; it's critical to test for these subtypes at diagnosis. Specifically, you want to test for mismatch repair, HER2, BRAF, and RAS [alterations]. These markers [may not impact frontline therapy] as much as [they would impact later-line therapies]; however, certain drivers do impact use of EGFR-targeted therapy. Additionally, tumor sidedness [impacts frontline treatment decisions]. In later-line settings, we have options for dMMR tumors with immunotherapy and we have targeted therapy options for HER2-amplified cancers, as well as for BRAF V600E—mutated cancers. We have really unique therapies for patients depending on the subtype of their cancer.

Could you expand on the frontline implications of tumor sidedness?

A correlation has been seen regarding the origin of the tumor and response to anti-EGFR therapy, especially in the frontline setting. Anti-EGFR therapy is of benefit in patients with left-sided RAS wild-type tumors. We don’t see a benefit [with this approach] in [those with] right-sided tumors. As such, we use [tumor sidedness] along with RAS status to determine who should receive anti-EGFR therapy. Those who should not will typically receive a VEGF-based targeted therapy.

How are you navigating through the treatment options currently available?

At the time of progression, we have standard second-line chemotherapies depending on what we used in the front-line setting, which is often oxaliplatin-based therapy. Often, we use irinotecan in the second-line setting. If we use a triplet with fluoropyrimidine, irinotecan, and oxaliplatin in the frontline setting, we can often reintroduce them at progression after maintenance therapy. That’s the classic kind of systemic chemotherapy [that we use] in the second-line setting. You could use targeted therapies for patients with BRAF-mutated, HER2-amplified, or MSI/dMMR tumors in the second-line setting; that’s where those options come into play.

After that, we have oral agents like regorafenib and TAS-102, which can both be used in third- and fourth-line refractory settings. Clinical trials are always an option as well.

Could you elaborate on the data reported with some of these targeted agents?

In terms of targeted therapy, we have data from the BEACON CRC trial in patients with BRAF V600E—mutant disease; that was the first randomized trial to include OS as an end point. The trial compared standard second-line FOLFIRI-based chemotherapy with either a triplet or doublet BRAF-targeted therapy.

The doublet was comprised of the BRAF inhibitor encorafenib and cetuximab, and the triplet consisted of encorafenib, cetuximab, and the MEK inhibitor binimetinib. We saw an improvement in OS with both the doublet and the triplet [over standard therapy]. Additional follow-up data that were presented at the 2020 Gastrointestinal Cancers Symposium showed similar OS in the doublet and triplet arms. The doublet probably has less toxicity, so I believe the data have really placed encorafenib and cetuximab as a key approach for patients with BRAF V600E mutations.

We don’t have any randomized data in the HER2 space yet, but we have a few different [combination] options such as trastuzumab/lapatinib (Tykerb) and trastuzumab/pertuzumab (Perjeta) from single-arm studies that have shown impressive activity. The randomized SWOG S1613 trial will randomize patients to receive either trastuzumab/pertuzumab or irinotecan/cetuximab.

We also have don’t have randomized data in the MSI-H/dMMR space. However, we’ve seen robust outcomes from single-arm studies of pembrolizumab or nivolumab, or the combination of nivolumab and ipilimumab that suggest that these are all appropriate options to use. The randomized KEYNOTE-177 study evaluated frontline pembrolizumab versus standard chemotherapy in patients with MSI-H/dMMR tumors; that trial completed almost 2 years ago, so we’ll likely have a readout from that study this year. That is a pretty exciting phase III study. The SWOG S1610 study is another frontline study that’s evaluating atezolizumab monotherapy, FOLFOX plus bevacizumab, and atezolizumab, FOLFOX, plus bevacizumab in patients with dMMR tumors.

How are you deciding between regorafenib and TAS-102 in the third-line setting?

We don’t really have data to make a clean distinction [between these agents], so [we base our decision on] the toxicity profile [of the agent. We consider] the characteristics of the patient as well as their concerns. Generally speaking, regorafenib tends to result in many adverse events that can be more challenging for patients, especially when it comes to fatigue. TAS-102 tends to be a little bit less [toxic] in that sense. There's not a right or wrong decision.

We can dose-escalate regorafenib to make the agent more tolerable for patients per the results of the ReDOS trial, which showed fairly equivalent outcomes with standard dosing and a dose-escalated approach. The main end point of the trial was the number of patients who reached cycle 3 of therapy, but several others showed similar outcomes between arms. Also, safety looked better with the dose-escalated approach.

Have you seen greater utility with regorafenib since the results of the ReDOS trial were reported?

The trial has helped us feel more comfortable in giving the medication safely. A number of patients ran into trouble on the full dose of regorafenib with a rapid and robust decline in functional status; that was pretty frustrating to many practitioners. This approach really lets us give the therapy in the third-line setting without the toxicity that's really detrimental to the patient. In some sense, the trial data have aided the utility of regorafenib because [we’re more comfortable] giving the agent now that has a more manageable toxicity profile.

Should any other important studies be highlighted?

We saw an update from a cohort of the single-arm CheckMate-142 study on the use of up-front nivolumab/ipilimumab in MSI-H/dMMR tumors. Nivolumab was given at a standard dose of 3mg/kg. Ipilimumab was given at a dose of 1 mg/kg every 6 weeks for a much longer duration. The outcomes [with this approach] look really good. We saw a robust 12-month PFS around 75%, which persists over time. The additional follow-up showed a consistent PFS benefit with the combination. Nivolumab/ipilimumab is very active and is an option for patients. It’s important to note that there’s no guideline indication for the combination, and the trial wasn’t randomized. Nonetheless, it is an interesting combination to consider and further supports the use of that combination [in the frontline setting] along with the refractory cohort from that study.

Is there rationale to explore immunotherapy in patients with MSS disease?

I’m fully supportive of investigating immunotherapy in patients with MSS disease; it’s worthwhile. Clearly, the vast majority of patients are MSS or proficient in mismatch repair. We do need to determine how to bring immunotherapy to those patients. It is a desperate need. The challenge is that we've tried a number of novel combinations that haven’t shown a lot of success. The complex microenvironment of CRC has held us back. It’s something we need to work on more to understand the factors at play. There’s ongoing work being done in that space.

One of the more encouraging preliminary combinations in that space is regorafenib plus nivolumab, updated data for which were presented at the 2020 Gastrointestinal Cancers Symposium. The results are encouraging, but the study was performed in a select group of patients from Japan and needs further confirmation before we say [this combination is] one to consider in clinical practice. Ongoing studies are evaluating that approach. In time, we'll have a better sense of how consistent the activity level of that combination is. At present, that's probably the combination that the majority of medical oncologists [who practice CRC] are probably most excited about in the MSS space.

What is your take-home message to your colleagues working in this space?

Those with [the above-mentioned types of molecular abnormalities] represent a good percentage of our overall mCRC population. It's really critical that we get the message out that that those [alterations] need to be tested [for], along with RAS [mutational] status.

References

1. Kopetz S, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab with or without binimetinib for BRAFV600E-mutant metastatic colorectal cancer: quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020;38(suppl 8; abstr 8). doi: 10.1200/JCO.2020.38.4_suppl.8
2. Kopetz S, Grothey A, Yaegar R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643. doi: 10.1056/NEJMoa1908075
3. Lenz H-J, Lonardi S, Zagonel V, et al. Nivolumab (NIVO): + low-dose ipilimumab (IPI) as first-line (1L) therapy in microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): clinical update. J Clin Oncol. 2019;37(suppl 15; abstr 3521). doi: 10.1200/JCO.2019.37.15_suppl.3521
4. Fukuoka S, Hara H, Takahashi N, et al. Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): an open-label, dose-finding, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2019;38(suppl 15; abstr 2522). doi: 10.1200/JCO.2019.37.15_suppl.2522
5. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi: 10.1016/S1470-2045(19)30272-4