Later-Line Treatment Approaches Make Headway in CRC Management

Axel Grothey, MD

The management of metastatic colorectal cancer (mCRC) continues to become more personalized, with care decisions being based on factors ranging from the patient’s primary tumor location, to performance status, to the presence of specific mutations, according to Axel Grothey, MD, and novel approaches emerging in later lines are helping to further improve outcomes.

“When we look at the benefits that we've seen for patients over the past 10 to 15 years and how we have improved overall survival (OS), we normally focus on first-line treatment; however, that's really not the full story,” said Grothey. “Patients benefit from getting access to all active agents over time in this continuum of care; that is why patients live longer nowadays compared with before.”

Agents such as regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf)have been shown to have play important roles in the third- and fourth-line setting, according to Grothey, and they are now being examined in novel combinations in an effort to elicit stronger responses. To this end, regorafenib is being evaluated in combination with nivolumab (Opdivo) and TAS-102 is being paired with bevacizumab (Avastin).

For patients with BRAF V600E-mutated disease, the combination comprised of encorafenib (Braftovi) and cetuximab (Erbitux)has become the new standard of care for this patient population, based on data from the phase 3 BEACON CRC trial. “Rightfully, the FDA approved the doublet and not the triplet,” said Grothey. “I like the doublet because there is less toxicity without binimetinib (Mektovi), it's cheaper, and this is combinable with chemotherapy.”

The emergence of the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) has also demonstrated promising clinical activity in patients with HER2-positive metastatic disease, according to Grothey.

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Grothey, a medical oncologist and director of Gastrointestinal Cancer Research at West Cancer Center and Research Institute, explained the impact of tumor sidedness on treatment decisions and highlighted novel later-line approaches that are under examination in colorectal cancer.

OncLive®: What are some of the factors that you consider when making care decisions in CRC?

Grothey: When we consider factors that influence treatment choices in mCRC, we normally talk about molecular markers. Specifically, we discuss KRAS, NRAS, HRAS, BRAF, and HER2 mutations, as well as microsatellite instability (MSI) status. However, I also believe [this decision goes somewhat] beyond that. We were able to individualize therapy before we had those molecular markers; [we would tailor treatment by considering] the patient’s age, performance status, and the goal of therapy.

Most recently, sidedness has become a very interesting factor that also influences our choices in terms of how aggressive [our treatment approach should] be. For example, we know that right-sided tumors are more aggressive and [these patients] have a poor prognosis. [Tumor location can also tell us] whether we [should] use EGFR antibodies in first- and second-line therapy.

Could you expand on how tumor location is being used to inform treatment? What are some of the data that have explored the impact of sidedness in this disease?

One of the more surprising findings that have surfaced in the past 5 years is that the location of the primary tumor really plays a role in tumor biology and how we should treat patients, in particular with regard to EGFR therapy. When we talk about left- and right-sidedness, the definitions [that we have are] not perfect and they differ in Europe and America. I [personally] trust the European definition and use the cut of the splenic flexure to distinguish between right- and left-sided tumors.

We've known that right-sided tumors are more aggressive. There is a prognostic implication that when right-sided tumors metastasize, patients have shorter survival. Based on studies that were done in the early 2000s, there can be about 5 months difference, which is quite significant. Once we looked at sidedness, examined the response of EGFR antibodies compared with bevacizumab. With trials such as the CALGB/SWOG 80405 study or the FIRE-3 study, we showed that right-sided tumors do not benefit from EGFR therapy, whether it's with cetuximab or panitumumab (Vectibix) up front. In contrast, we found that bevacizumab is kind of sidedness agnostic, so we can use this agent in right-sided tumors. That is quite interesting because there might even be a detrimental effect that is suggested when we use cetuximab in right-sided tumors; that's why the National Comprehensive Cancer Network (NCCN) guidelines do not recommend using cetuximab or panitumumab in right-sided tumors.

How are regorafenib and TAS-102 being used in the later-line setting? How do you select which agent to use first?

These 2 drugs are very important, even though we recognize that they only have moderate activity. Both are not breakthrough agents and do not really induce many responses in the majority of patients. When you compare the progression-free survival (PFS) curves, they're really [comparable].

Regorafenib and TAS-102 stand about side-to-side as third- and fourth-line treatment options, whether it’s per NCCN or other guidelines. What really distinguishes [regorafenib from TAS-102] are the different toxicity profiles. With regorafenib, patients [experience] hand-foot-skin reactions, fatigue, voice changes, and some diarrhea. The main toxicity [experienced with] TAS-102 is neutropenia, to the extent that many patients cannot continue treatment on the same schedule after 4 weeks when they come back for their second cycle. The question that we have right now during the time of the novel coronavirus disease 2019 pandemic is whether neutropenia is the desired AE when you compare regorafenib with TAS-102.

Regorafenib is not appropriate for patients with a performance status of 2 because of the subjective AEs that they experience. The pool of patients who are candidates for treatment is larger for TAS-102. My concern is that when we start with TAS-102, we potentially allow patients to deteriorate in their performance status, and they might never become candidates for regorafenib. We are much more likely to [be able to] give both agents when we start with regorafenib and then go to TAS-102.

How are these agents being used in combination regimens?

Last year, a dataset of a phase 1b Japanese study was presented; this trial evaluated regorafenib at a low dose of 80 mg plus nivolumab in patients with CRC and gastric cancer. Some of the [patients with] gastric cancer had been pretreated with nivolumab and experienced disease progression. Results showed a remarkable response rate of over 30% for both cohorts; unfortunately, [this benefit] has not been replicated yet in a Western population. The Japanese population had many patients with rectal cancer and lung metastases, which we know have a different immune environment and might respond better to augmented immunotherapy. This idea of a combination of a multikinase inhibitor plus a PD-1 antibody is actually quite intriguing because we've seen data in other cancers for lenvatinib (Lenvima), which is a similar agent compared with regorafenib, plus pembrolizumab in endometrial cancer and microsatellite stable (MSS) endometrial cancer; this regimen was actually approved. We've also seen it in liver cancer and we've seen data in gastric cancer. This idea of a multikinase inhibitor activity and a PD-1 antibody is quite interesting.

Another combination to mention is TAS-102 with bevacizumab. The active component of TAS-102 is trifluridine, which is a fluoropyrimidine. We know that bevacizumab plays very nicely with fluoropyrimidine. We have data from a later-line randomized Danish trial with TAS-102 with or without bevacizumab. [Just under] 100 patients [were included] but a significant improvement in PFS and OS with good tolerability [was observed with the combination].

Additionally, a recent publication in Annals of Oncology spotlighted a European study, which compared capecitabine plus bevacizumab with TAS-102 plus bevacizumab. [This was] a randomized trial that was done in patients who are not candidates for oxaliplatin or irinotecan. Those patients experienced a numeric difference in benefit from TAS-102 over capecitabine when bevacizumab was added. We have later-line data and early-line data, but in my patients, I try to include bevacizumab in their treatment when TAS-102 is used.

Could you discuss some of the other combinations that have been explored in the later-line space? What were the results from the BEACON CRC trial?

Patients with a BRAF V600E mutations in mCRC constitute about 8% to 20% of all patients; this population represents an unmet need because they have a very poor prognosis. We've also realized that these BRAF mutations really activate the MAPK pathway, which has a feedback loop to the EGFR antibody when you block just 1 of the components of the pathway. Based on a lot of translation data and early clinical data, we realized that we need a BRAF inhibitor, an EGFR antibody, and potentially a MEK inhibitor on top of that; [essentially], a biologic doublet or triplet, to shut down this activating pathway in BRAF V600E-mutant tumors.

This is exactly what was investigated in the phase 3 BEACON CRC study, which is a phase 3 study done in the second- and third-line setting, which included approximately 600 patients, with about 200 enrolled to each arm. [Patients were randomized to] the old standard of care of an irinotecan-based therapy with cetuximab, or a biologic doublet of encorafenib, a BRAF inhibitor, plus cetuximab, an EGFR antibody, or a triplet [comprised of encorafenib, cetuximab], and the MEK inhibitor binimetinib.

The initial data, which were published in the New England Journal of Medicine last year, showed that both the doublet and triplet beat the old standard of care in that they led to a significant improvement in response rate, PFS, and OS. The updated analysis with more data showed that the addition of binimetinib did not contribute at all to efficacy. When you plotted the OS data, [you saw] a median of 9.3 months, which is really remarkable for a second- and third-line setting; both the doublet and triplet arms had the exact same outcome.

The next study will either combine the doublet with chemotherapy or examine [this regimen] as a freestanding option in the first-line treatment setting. The BREAKWATER study is currently being designed, and there are also efforts to have this well-tolerated doublet moved into the adjuvant setting to potentially cure more patients.

Could you speak to the rationale of exploring trastuzumab deruxtecan in CRC?

We are seeing excitement in the HER2 world—not just in CRC, but in gastric and breast cancer—with an ADC that has shown remarkable activity in these 3 tumor types. The agent even [has activity] in patients who have been pretreated with HER2-targeted agents, such as trastuzumab (Herceptin) plus or minus other combinations.

In the DESTINY-CRC01 study, investigators examined trastuzumab deruxtecan in patients in a later-line setting. It was a phase 2 study that looked at different cohorts. In cohort A, patients had overexpressing HER2. Patients in cohorts B and C had lower expression of HER2; those tumors did not have any responses. However, significant activity was shown in patients with immunohistochemistry 3+, with response rates over 50%. These responses were longer lasting, even in patients who had been pretreated with HER2-targeted agents, such as trastuzumab or trastuzumab plus pertuzumab (Perjeta). [These are] very interesting data, showing high and long-lasting activity, validating HER2 as a target for our treatment approaches in CRC.

The problem with this study was that this drug has an AE that we need to pay attention to: interstitial lung disease (ILD). Two patients out of the 70 included in the study experienced a fatal complication. We've seen this AE in the breast cancer studies and in the gastric cancer study; however, this led to fatality in the CRC study. We need to monitor this toxicity very closely. There's a whole effort to diagnose patients early and to develop guidelines on how to manage them so that they do not experience a grade 5 toxicity here

What is your take-home message on the current state of CRC treatment?

It's really exciting to be in the field of oncology, overall. In gastrointestinal oncology, CRC in particular, there's so much happening right now. We're embracing early molecular profiling to find the right treatment approaches for patients. We’re very excited about immunotherapy for MSI-H tumors, and hopefully, at some point, we will find the holy grail, which is making MSS tumors responsive to immunotherapy. This would be moving the field even further forward. Overall, I'm very excited about the field and I hope I can share the excitement with everyone who's out there treating these patients.