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Manji Advises on Community Oncologists Targeting Molecular Markers in Patients with Colon Cancer

Nichole Tucker
Published Online:1:00 PM, Mon August 19, 2019
Gulam A. Manji, MD
Gulam A. Manji, MD
The treatment paradigm for colon cancer is evolving, according to Gulam A. Manji, MD. As researchers continue to identify new molecular markers, treatments are emerging that can target certain markers and alterations.

For example, as of recently, 2 drugs have been approved by the FDA for the treatment of patients with NTRK fusions across tumor types, larotrectinib (Vitrakvi) and entrectinib (Rozlytrek). Although NTRK fusions are rare in colon cancer and other gastrointestinal (GI) malignancies, a targeted therapy with efficacy in this patient population is promising to have.

Additionally, for patients with BRAF-mutated colorectal cancer, the combination of the BRAF inhibitor encorafenib (Braftovi), the MEK inhibitor binimetinib (Mektovi), and the EGFR inhibitor cetuximab (Erbitux) is emerging as a promising triplet in this patient population due to findings from the phase III BEACON CRC trial.

For patients with microsatellite instability (MSI)–high colorectal cancer, 2 immune checkpoint inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda) are approved to treat this specific patient population, and newer combinations with these PD-1 inhibitors are also in development.

However, there are many patients with colon cancer who have molecular markers that do not yet have available matched targeted therapies. Manji believes that the key to improving outcomes for this patient population is enrolling them in clinical trials. More importantly, these patients should get the treatment they need early on, rather than waiting for progressing on first-line chemotherapy.
 
In an interview with Targeted Oncology following his presentation at the 3rd Annual Congress on Oncology & Pathology hosted by PER®, Manji, director of medical oncology and translational research for the pancreas center, Columbia University Irving Medical Center, discussed the emergence of new therapies for targeting mutations in patients with colon cancer.

TARGETED ONCOLOGY: How has our ability to target mutations and alterations in colon cancer impacted the outcomes for patients?

Manji: I think that with the identification of new mutations that seem to be actionable and the evolving paradigm of having new clinical trials that are showing small glimpses of hope with active combination regimens is very exciting, 

In particular for patients with BRAF mutations and patients with NTRK translocations and fusions, the future is very bright. 

Unfortunately, a small proportion of patients with NTRK translocations have GI malignancies. So, the majority of the patients cannot benefit [from these targeted therapies]. The good thing is that we keep on cutting away at the pie [of targetable alterations] and chipping away at this population and it's encouraging. 

TARGETED ONCOLOGY: What are the treatment options for BRAF-mutant colon cancer?

Manji: In patients with BRAF mutations, the prognosis is worse than for many of the other mutations in colon cancer. However, recent combination trials that target EGFR, MEK, and BRAF are showing great promise with improved response rates and a good progression-free survival.

So, all patients who have BRAF mutation should be enrolled in these clinical trials so that we can get solid data that shows proven benefit. 

TARGETED ONCOLOGY: What are the treatment options for NTRK fusions?

Manji: For NTRK fusions, the [drugs are] histology-agnostic, which is fantastic, and it's already approved. These patients can now just take a targeted inhibitor. There are multiple inhibitors that are already coming onto the market and [two] of them are already FDA approved. These patients are showing durable responses and [this is a] population that is already heavily pretreated. So, the future for NTRK translocation patients is fantastic. 

TARGETED ONCOLOGY: What is the difference in prognosis between patients with right-sided colon cancer and those with left-sided colon cancer.

Manji: Patients who have right-sided tumors tend to have an increased amount of BRAF mutations, while patients with left-sided tumors [are more likely to have] HER2-positive disease.

However, when looking at the subgroup analysis of patients who have already been treated with chemotherapy in combination with EGFR-directed therapy, it appears that patients with right-sided tumor do not benefit from EGFR-directed combinations. So, at least in the first line, patients with right-sided tumors, regardless of whether they have a KRAS mutation or not, should not be treated with EGFR-directed therapy. Instead, they should be treated with VEGF-directed therapies or chemotherapy in combination with bevacizumab (Avastin).  

TARGETED ONCOLOGY: How should oncologist treat patient with MSI-high colon cancer?

Manji: Patients with MSI-high who have gone beyond chemotherapy should be treated with immunotherapy such as pembrolizumab and nivolumab. Now, [these therapies] can be combined, cytotoxic T-lymphocyte-associated protein-4 with programmed cell death-1 directed therapy. 

TARGETED ONCOLOGY: How much of an impact is immunotherapy having on patients with MSI-high colon cancer?

Manji: Not all patients who are MSI-high are responding to immunotherapy or even checkpoint blockade, but a majority of them are. [Patients who are responding have durable response]. This is very promising. 

TARGETED ONCOLOGY: Looking at the majority of patients with colon cancer, what is your outlook on the treatment landscape?

Manji: Unfortunately, for the majority of patients, we need to continue looking for these additional mutations that may be actionable and further impact their survival and efficacy. Other than KRAS mutations, we don't have a large proportion of patients who have a certain mutation for which we have effective therapy. 

For example, for patients with NTRK mutations, there are these rare diseases where there's a large proportion of patients who have the mutation, so they can benefit. Unfortunately, for GI malignancies, that was not the case. 

For gastrointestinal stromal tumors, particularly in tumors that don't have a c-kit mutation or a PDGFRα mutation, the percentage of those tumors have a decent amount of NTRK translocations. So, we may have some efficacy there. 

TARGETED ONCOLOGY: What do you want community oncologists to take away from your presentation on molecular markers and the treatment paradigm for colon cancer?

Manji: Looking at all GI malignancies, we're starting to get a handle on targetable mutations where we are seeing significant activity. For oncologists in general, it is very important to keep your finger on the pulse [when treating] this difficult to treat patient population. See where new clinical trials are showing some encouraging results and try to identify trials for these patients so they can benefit. 

The key is not to wait until the patient has progressed on first-line chemotherapy. Start looking for trials when these patients are started on first-line chemotherapy. So, you hope for the best but prepare for the worst and you have something ready for them when that time comes.

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