Targeted Treatments Usher in Individualized Care in mCRC

Jonathan Mizrahi, MD

The standard of care for patients with metastatic colorectal cancer (mCRC) can continued to be improved through better use of molecular testing, explained Jonathan Mizrahi, MD.

As more molecular subsets are defined, and additional targeted therapies are developed, the importance of understanding the underlying genomic makeup of a patient’s tumor is becoming increasingly important.

Two examples of this research focus were presented at the 2019 Gastrointestinal Cancers Symposium, both of which confirmed the benefit of targeted therapy for patients with identifiable genomic abnormalities, such as BRAF V600E—mutant and microsatellite stable (MSS) disease. Updated results from the safety lead-in portion of the phase III BEACON CRC trial showed that the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) induced a high objective response rate (ORR) of 48% in patients with BRAF V600E—mutant mCRC by local assessment, surpassing historical ORRs of <10%.¹

Moreover, data from a randomized phase II trial indicated a modest, although unexpected, benefit with the combination of durvalumab (Imfinzi) and tremelimumab in patients with MSS mCRC. Results from the CCTG CO.26 trial showed a 34% reduction in the risk of death when the combination was added to best supportive care versus supportive care alone (HR, 0.66; 90% CI, 0.49-0.89; P = .024) in this subgroup.²

“We have to test patients early—when they’re still fit, when they still have a good performance status, and when they don’t have any lab abnormalities that would prohibit them from enrolling on a trial. I would argue that you should do it at diagnosis,“ said Mizrahi.

“You can tell the patient, ‘Let’s go ahead and get this. It can be on the back burner for now, but we’ll have it available when we’re thinking about progression and what we’re going to do in the next line of therapy.’”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Mizrahi, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, shared updates from the 2019 Gastrointestinal Cancers Symposium and their impact on personalized care in CRC.

OncLive: What were the most impactful updates in CRC from the 2019 Gastrointestinal Cancers Symposium?

Mizrahi: One exciting study looked at the use of durvalumab and tremelimumab. This was a study of PD-L1 inhibition and CTLA-4 inhibition in a refractory patient population. Investigators looked at all-comers and saw an overall survival (OS) benefit, irrespective of PD-L1 status and microsatellite instability—high (MSI-H) status. The OS difference was small, but it is a positive study. It will be interesting to see what the uptake of that combination will be in the general public if it’s approved. We also got more data on the BEACON CRC study, which is looking at the combination of encorafenib, binimetinib, and cetuximab in patients with BRAF-mutated disease. We’re still waiting on the final mature data, but the preliminary results look really great. It will probably be the standard of care for that group ofpatientssoon.

What is the importance of personalized therapy in CRC?

Personalized therapy is key. We have a limited repertoire of cytotoxic chemotherapy agents that work for everyone. We know that 5-fluorouracil—based regimens with the addition of oxaliplatin and irinotecan work. We also have regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) in the refractory setting.

Adding biologic agents, such as cetuximab, is a prime example of individualized therapy. Is your tumor left-sided or is it right-sided? Does it harbor a KRAS/NRAS mutation? You have to know that before you decide on [what] the best therapy [will be]. Then, you look at patients with BRAF mutations, and you have to figure out what the best combination of BRAF/MEK inhibition could be for them. You have patients who have MSI-H tumors; you have patients who have deficient mismatch repair proteins, [in whom] we know immunotherapy works best. We’re looking at HER2-targeted therapy [for those with HER2 expression]; at 3% to 4%, these patients represent a small subset of the overall population.

To get to the next step with molecular targeted therapies, we need to sequence these patients. As we do that, we’ll find more targets and we’ll develop more drugs.

What challenges still need to be addressed?

We need to send genomic molecular-based panels of tumors so that we can identify the patients with these mutations. Then, we can enroll these patients in clinical trials early. If we wait for patients to progress on multiple lines of therapy, their performance status may be worse by the time they’re referred to a clinical trial center.

It’s crucial to implement genomic molecular testing early in patients with mCRC. Testing early is always appropriate. Unlike with an oligometastatic patient in whom cure is still possible, whenever you’re dealing with a metastatic patient, we’re talking about a palliative setting. These are patients who will run through all lines of available therapy, assuming they’re fit enough, after which we’ll want to enroll them in a clinical trial.

You also coauthored a paper on bevacizumab (Avastin) as a chemotherapy protectant. Could you discuss the findings from the study?

Michael Overman, MD, of The University of MD Anderson Cancer Center, and I looked at therapies that could potentially, when added to oxaliplatin, reduce the liver injury that is caused by oxaliplatin. Oxaliplatin is known to cause hepatic sinusoidal injury, which manifests in reduced platelets and splenomegaly. It’s something that’s often seen when we do hepatic resections and metastasectomies. A patient with limited liver metastases may have a metastasectomy. On their pathologic sample, we’ll see evidence of hepatic sinusoidal injury, which is due to the oxaliplatin.

We’ve seen that patients who are treated with preoperative bevacizumab and oxaliplatin [in a regimen like FOLFOX, for example] have lower rates of hepatic sinusoidal injury. We think that bevacizumab is a protectant by way of the VEGF inhibition interaction with the reactive oxygen species. We know that patients who have hepatic sinusoidal injury have increased morbidity after they have liver resection with metastasectomy. If preoperative bevacizumab becomes an option, we believe it would be beneficial for patients.

References

1. Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). J Clin Oncol. 2019;37(suppl 4, abstr 688). doi: 10.1200/JCO.2019.37.4_suppl.688.
2. Chen EX, Jonker DJ, Kennecke HF, et al. CCTG CO.26 trial: a phase II randomized study of durvalumab (D) plus tremelimumab (T) and best supportive care (BSC) versus BSC alone in patients (pts) with advanced refractory colorectal carcinoma (rCRC). J Clin Oncol. 2019;37(suppl 4; abstr 481). doi: 10.1200/JCO.2019.37.4_suppl.481.