Lenz Highlights Ongoing Advances in mCRC

Heinz-Josef Lenz, MD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in the frontline setting of microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) is one of a number of regimens eagerly awaited to read out in the field, according to Heinz-Josef Lenz, MD.

In July 2018, the FDA granted an accelerated approval to the PD-1/CTLA-4 inhibitor 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. The frontline data will be presented at the 2018 ESMO Congress.

“We are living in the middle of a molecular revolution of colorectal cancer,” said Lenz. “We have learned a lot about the molecular genetics in colon cancer and how this will translate into treatment decisions in everyday clinical practice. There is so much more to come.”

Additionally, the FDA granted a breakthrough therapy designation in August 2018 to the combination of the BRAF inhibitor encorafenib (Braftovi), the MEK inhibitor binimetinib (Mektovi), and the EGFR inhibitor cetuximab (Erbitux) for BRAF V600E—mutant mCRC. The designation was announced based on data from the phase III BEACON CRC trial (NCT02928224), which demonstrated an ORR of 48% and a 1-year overall survival (OS) rate of 62%.

OncLive: How has treatment for patients with mCRC changed in recent years?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, Lenz, associate director for Adult Oncology and co-leader of the Gastrointestinal Cancers Program, University of Southern California Norris Comprehensive Cancer Center, discussed the intersection between the molecular makeup of CRC and the development of novel therapies in the treatment paradigm.Lenz: We have just scraped the surface of CRC with DNA mutational analyses. Now, we have gene expression analyses showing that these may even be more helpful in the future. [In my presentation], I spoke about the future in the treatment of [patients with] mCRC in terms of integrating novel and cutting-edge technology, such as liquid biopsy. That will come; it is already used in many clinical practices and is giving us insight into molecular monitoring.

The testing of molecular genetic makeup at the time of diagnosis is done everywhere. The only question is, “How extensive would the panel be?” With liquid biopsy, we can now capture not only the heterogeneity of different metastatic sites, but [also test patients] at the time of progression of disease, [so we know] what their molecular genetics are. This makes it easier to decide what potential treatment options patients have.

[We have a] completely new way of monitoring our patients with metastatic disease and identifying potential novel targets. We are very excited about these opportunities. Of course, integrating the novel targeted treatments, such as immunotherapy for MSI-H mCRC, which will be moved into the first-line setting. We will present these data at the 2018 ESMO Congress showing incredibly promising data.

We also reviewed the new treatments for HER2-directed colon cancer. HER2 is usually only seen or treated in gastric and breast cancer, but we know up to 10% of patients with CRC receiving EGFR-targeted treatment can develop HER2 alterations. The efficacy of HER2-targeted drugs is extremely promising. BRAF-mutant CRC is one of the poorest prognostic markers we know of in metastatic disease.

What is the overall benefit with regorafenib (Stivarga), and how will it evolve as new agents come to the forefront?

We have newer treatment options without classical chemotherapy that are showing high response rates and long progression-free survival (PFS). I have no doubt that this will also move into first-line treatment in the years to come.Regorafenib is a multikinase inhibitor that has efficacy in refractory disease. One of the most surprising facts is that this antiangiogenic drug has efficacy even when patients were previously treated with bevacizumab (Avastin). It captures some of the escape mechanism with its targets. We have struggled with the prior recommended dose of 160 mg, as it can be toxic.

Learning and adjusting to the side effect profile and the timing of the adverse events (AEs) is critical. When you monitor on a weekly basis, you can capture it early enough. If the AE happens, it will happen in the first couple of weeks, not later on. There was always an ongoing discussion whether we should start all patients with 160 mg or 120 mg. Many of my peers, including myself, started with 120 mg.

Are there any new developments with TAS-102 (Lonsurf)?

The ReDOS study, which we participated in, showed that you can start with 80 mg and if you don't see any dose-limiting toxicity, you can go to 120 mg and potentially 160 mg. The data presented this year showed that this is feasible and leads to longer PFS. The reason is that you can safely give the drug; it doesn't lead to significant dose interruptions, which can last 1 to 3 weeks. Safer dose escalation with the ReDOS study showed us that it does not jeopardize the outcome and improves outcomes for this patient population. Most trials and clinical practices have adjusted very quickly to the new ReDOS schedule.With TAS-102, there are some developments, particularly with combinations. There are trials showing a very promising survival benefit with TAS-102 and bevacizumab compared with capecitabine and bevacizumab.

What are your thoughts on the triplet encorafenib, binimetinib, and cetuximab that was granted breakthrough designation status?

[A question that remains is whether that combination should be moved into] earlier lines of treatment, because this study was done for patients with newly diagnosed metastatic disease not fit for classical doublet or triplet chemotherapy.For BRAF-mutant patients, this is a big change because multiple studies showed [benefit with] the triplet combination of a BRAF inhibitor in the center with a MEK inhibitor. Previously, it was also tested with PI3K inhibitors and with VEGF-receptor inhibitors. In this case, cetuximab showed very promising results. In refractory patients, response rates over 30% were seen, which is unheard of.

What are other strategies for the BRAF-mutant population would you like to see?

Recent data presented at the 2018 World Congress on Gastrointestinal Cancer showed not only high response rates, but long PFS and OS. That is the reason that there is a trial being developed in the first-line setting. The interesting thing is that this triplet has no cytotoxins—only targeted agents. This indicates that when you are smart in identifying the molecular genetics of the tumor, you can successfully interfere and have dramatic clinical effect without a lot of toxicities.This triplet is by far the most promising regimen. The question is, “How quickly we can get it in first-line setting?” SWOG 1406 investigated the BRAF inhibitor cetuximab and irinotecan with or without vemurafenib (Zelboraf) and showed significant survival benefit over irinotecan and cetuximab in these patients. That led to the integration of BRAF inhibitors into the National Comprehensive Cancer Network guidelines.

What other immunotherapy updates are you excited to hear about?

BRAF-mutant tumors are very interesting. Their immune responsiveness is being questioned. Should we combine BRAF inhibitors with immune therapies or other agents? [Combining it with a MEK inhibitor] may not be the best. ERK inhibitors may be more promising. Recent data from Ryan B. Corcoran, MD, PhD, that were published in Cancer Discovery, fully support the data that the triplet with an ERK inhibitor and a PD-1/PD-L1 inhibitor may be very promising.For MSI-H tumors, [we’ll see] the effect of nivolumab and ipilimumab when the data are presented at the 2018 ESMO Congress. [That combination] has a chance to get to first-line treatment because the efficacy data seem to be very convincing. For microsatellite stable tumors, should we combine immunotherapy with standard chemotherapy—FOLFOX/bevacizumab with nivolumab? These trials are all ongoing. For MSI-H tumors, we don't know if immunotherapy will work in the adjuvant setting. Here, the question is, “Should we give FOLFOX and immunotherapy?” This is a cooperative group [study] in the United States that is going to test the benefit in this patient population.

Array Biopharma receives FDA breakthrough therapy designation for Braftovi™ in combination with Mektovi^® and cetuximab for BRAFV600E-mutant metastatic colorectal cancer. Array BioPharma Inc. Published August 7, 2018. https://bit.ly/2vJUhEA. Accessed August 7, 2018.