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%.
In an interview during the 2018 OncLive®
State of the Science SummitTM
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.
OncLive: How has treatment for patients with mCRC changed in recent years?
: 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.
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.
What is the overall benefit with regorafenib (Stivarga), and how will it evolve as new agents come to the forefront?
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.