Grothey Spotlights Personalized Approaches Shaking Up CRC Care Continuum

Axel Grothey, MD

With immunotherapy targeted combination regimens, and a novel antibody-drug conjugate (ADC), the colorectal cancer (CRC) paradigm is bursting with personalized options, according to Axel Grothey, MD.

“We are beyond the one-size-fits-all treatment approach for patients with CRC. We must embrace molecular profiling in all patients with gastrointestinal malignancies because we now have many drugs available that can target specific disease types,” said Grothey. “This can be done effectively with fewer toxicities, when compared with chemotherapy. Ultimately, this is a new era of oncology, and we see more improvements each year.”

Based on data from the phase 3 KEYNOTE-177 trial (NCT02563002), which showed that single-agent pembrolizumab (Keytruda) resulted in a doubling of progression-free survival (PFS) versus standard chemotherapy, the immunotherapy has become the new frontline standard for patients with microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) metastatic CRC.¹ “However, we need to understand that there is a subgroup of patients who do not benefit from pembrolizumab, even though they express dMMR,” said Grothey. “We need to perform trials that will help us identify these patients.” An additional analysis presented during the 2021 Gastrointestinal Cancers Symposium demonstrated that patients treated with pembrolizumab experienced better health-related quality of life. Moreover, the PD-1 inhibitor reduced the risk for progression on next-line therapy by 37%.²

For patients with BRAF V600E–mutant metastatic CRC, data from the phase 3 BEACON CRC trial (NCT02928224) showed that a regimen composed of encorafenib (Braftovi) and cetuximab (Erbitux) with or without binimetinib (Mektovi) improved overall survival (OS) and objective response rates (ORRs) compared with standard chemotherapy.³ The median OS was 9.0 months with the triplet, 8.4 months with the doublet, and 5.4 months with the control regimen; the ORRs in these arms were 26%, 20%, and 2%, respectively. However, data from the updated analysis revealed that the median OS was 9.3 months for both the triplet and the doublet.⁴ “As such, right now, the FDA has endorsed encorafenib and cetuximab as a standard of care,” noted Grothey.

Lastly, the ADC fam-trastuzumab deruxtecan-nxki (Enhertu) has generated excitement, after having demonstrated a confirmed ORR of 45.3% (95% CI, 31.6%-59.6%) in patients with HER2-overexpressing unresectable and/or metastatic CRC, according to data from the DESTINY-CRC01 trial (NCT03384940).⁵ “For me, this is the most exciting HER2targeted agent in CRC, as well as in other diseases, such as gastric cancer and breast cancer,” said Grothey.

In an interview with OncLive^® during a 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, highlighted recent advancements in CRC treatment, including innovative combinations and emerging agents in the field.

OncLive^®: What are the lessons from the KEYNOTE177 trial regarding the use of immunotherapy in patients with MSI-H disease?

Grothey: The KEYNOTE-177 trial randomized patients with MSI-H or dMMR stage IV CRC to frontline pembrolizumab or investigator’s choice of standard -of-care chemotherapy. These patients account for only 5% of [all patients] with CRC. However, once they’re identified, these patients have a great treatment option in the form of immunotherapy.

This trial involved about 300 patients and clearly showed that PFS, a coprimary end point with overall survival [OS], was relevantly improved with the use of pembrolizumab over chemotherapy. The median PFS more than doubled [on the immunotherapy arm], and there was a hazard ratio of 0.60. This was an interesting phenomenon that had a caveat: The curves actually crossed.

There appears to be a subgroup of patients who do better with chemotherapy initially, when compared with pembrolizumab. These curves cross at about 6.5 months, which means that, until that point, pembrolizumab is actually slightly detrimental. It then crosses over and provides a long-term PFS benefit. This trial also showed a higher rate of patients having disease progression as best response on pembrolizumab; this was about 29.4% compared with 12.3% [of those on] chemotherapy.

What questions have been left with this research?

We need future studies that will identify the patients who will not benefit from pembrolizumab. Do they have lower tumor mutational burden? Do they have RAS mutations? Do they express other features that we have not yet identified? Those patients might actually benefit from pembrolizumab [plus] chemotherapy, at least initially. This is similar to an approach that is being utilized in the lung cancer field.

Are you excited about any other investigational combination regimens under exploration for MSI-H tumors?

Many combination approaches are being investigated right now [for these patients]. [Of course,] there is the combination of PD-1 antibody therapy plus chemotherapy, but we are also exploring PD-1 antibody therapy plus CTLA-4 inhibition. [For example], nivolumab [Opdivo] plus ipilimumab [Yervoy] seems to be quite active, even in the first-line setting. We have some single-arm phase 2 data on this [regimen]. This is clearly an exciting time, and we’re always happy to see MSI-H expression in a tumor because it truly opens the door for durable responses. I strongly believe that patients with metastatic MSI-H CRC can be cured with immunotherapy, because the durability of response is so long. We don’t see this with chemotherapy.

Another novel combination regimen was explored in patients with BRAF V600E–mutant disease as part of the BEACON trial. What was the significance of this research?

When it comes to BRAF V600E–mutant tumors in CRC, the ones that have the poorest prognosis, we know that firstline treatment might work with conventional chemotherapy. However, second- and third-line treatment activity is very limited. We recently developed an approach to biologically target the BRAF V600E mutation and inhibit a feedback loop that is activated by BRAF: combining a BRAF inhibitor with an EGFR antibody. This is the backbone of the phase 3 BEACON trial, which was recently published.

We now have a new standard of care in the first- and second-line settings for BRAF V600E–mutant tumors: combining the BRAF inhibitor, encorafenib, with an EGFR antibody. In the BEACON trial it was cetuximab [Erbitux], but the National Comprehensive Cancer Network guidelines also allow [the use of] panitumumab [Vectibix]. We see higher response rates [with this combination] versus conventional chemotherapy, along with a longer PFS and OS benefit.

The BEACON study initially investigated the addition of a MEK inhibitor to this biologic regimen; however, in further follow-up, we showed that this addition did not improve survival. The fact that we can get away with a biologic doublet is encouraging because the toxicity profile is very tolerable and moderate. Now, the ongoing BREAKWATER study [NCT04607421] will target patients with BRAF V600Emutant tumors with encorafenib plus cetuximab, either alone or in combination with chemotherapy.

The ANCHOR trial is often considered to be a cousin of the BEACON CRC study. How did the combination perform when moved to the frontline setting?

The BEACON trial looked at the combination of a BRAF inhibitor and an EGFR inhibitor in patients with BRAF V600Emutant tumors in the second-line setting. The ANCHOR trial [NCT03693170] evaluated the same combination but in the first-line setting. Currently, we don’t have any randomized data. We have a single-arm cohort study of about 40 patients. We saw activity in terms of response rates, which were around 50%. In fact, [all patients experienced tumor] shrinkage. This is strong activity for the f irst-line setting; however, the [median] PFS was only about 4.9 months, which is disappointing. This probably points to the fact that, if we inhibit BRAF, including the feedback inhibition with an EGFR antibody, tumor cells are still finding ways to become resistant. As such, we must closely evaluate the mechanisms of resistance.

How do you approach the treatment of patients with BRAF-mutant, MSI-H tumors in practice?

With the BEACON regimen, patients showed rapid progression of disease after a certain period of time; [these are] not the long-lasting responses that we have seen with immune checkpoint inhibitors. This is a great lesson for us because we have many patients who have BRAF-mutant disease and MSI-H tumors. My regimen of choice is immune checkpoint inhibitors, such as pembrolizumab, or combinations such as nivolumab and ipilimumab.

Beyond these combination regimens, a novel ADC has emerged in the paradigm. Could you speak to the data reported with trastuzumab deruxtecan in patients with HER2-overexpressing tumors?

In this trial, patients with HER2-overexpressing tumors received trastuzumab deruxtecan, an ADC that links trastuzumab with a strong topoisomerase inhibitor as a payload, which then gets integrated into the cells. When the linker between the antibody and the topoisomerase inhibitor gets cleaved, the cytotoxic agent gets released. The hope is that [when this happens,] the cell will die and there will be a bystander effect on surrounding cells.

This trial investigated trastuzumab deruxtecan in patients with HER2-overexpressing CRC in a later-line setting. Many of these patients were pretreated with HER2-targeted agents. Interestingly, in patients with high HER2 overexpression, the ADC showed significant responses, which were around 45%, independent of pretreatment with HER2-targeted agents. Some of these responses were durable.

How does this activity compare with other HER2targeted strategies that have been examined in this space?

This is probably the most impressive activity of all HER2- targeted agents and approaches [we have seen]. Based on prior studies, such as [My Pathway; NCT02091141], which combined trastuzumab [Herceptin] and pertuzumab [Perjeta], as well as MOUNTAINEER [NCT03043313], which evaluated trastuzumab and tucatinib [Tukysa], we have seen the activity of anti-HER2 agents in HER2-positive CRC. However, the activity of this ADC seems to be more profound and longer lasting, and it works in patients who were not previously pretreated with HER2-targeted agents.

References

1. FDA approves Merck’s Keytruda (pembrolizumab) first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer. News release. Merck. June 29, 2020. Accessed January 20, 2021. bwnews.pr/3ePxyfu.
2. Kopetz S, Grothey A, Yaeger 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. Kopetz S, Grothey A, Van Cutsem E, et al: Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: quality-of-life results from a randomized, three-arm, phase III study vs the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol. 2020;38(suppl 4):8.doi:10.1200/JCO.2020.38.4_suppl.8
4. Siena S, Bartolomeo MD, Raghav K, et al. A phase 2, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-expressing metastatic colorectal cancer: DESTINY-CRC01. J Clin Oncol. 2020;38(suppl 15):4000. doi:10.1200/JCO.2020.38.15_suppl.4000