Tumor Sidedness Opens Door for Personalized Therapy in Colorectal Cancer

Sujatha Nallapareddy, MD

A better understanding of colorectal cancer (CRC) biology has allowed for more opportunities for personalized treatment approaches, which, in turn, has improved overall survival (OS) for patients, said Sujatha Nallapareddy, MD. However, more progress is needed in terms of identifying predictive biomarkers and effective combination strategies.

The CALGB/SWOG 80405 trial painted a clearer picture of the differences between right- and left-sided disease and how physicians can better tailor therapy to patients based on tumor location. In the study, researchers found that patients with KRAS wild-type CRC with a left-sided tumor had superior OS and progression-free survival (PFS) compared with those who had right-sided disease. Moreover, the study showed that survival was prolonged with the addition of cetuximab (Erbitux) to chemotherapy in those with left-sided CRC and with bevacizumab (Avastin)/chemotherapy in patients with right-sided disease.

Furthermore, in the overall population, median OS for patients with left-sided tumors was 34.2 months compared with 19.4 months in those with right-sided tumors. In patients treated with cetuximab, having a left-sided tumor led to a median OS of 37.5 months compared with 16.4 months in those with right-sided disease. Patients with right-sided CRC had better outcomes on bevacizumab than they did with cetuximab; however, left-sided patients still experienced a longer median OS on cetuximab at 32.1 months versus 24.5 months.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Nallapareddy, a gastrointestinal medical oncologist at Rocky Mountain Cancer Centers, discussed how personalized therapy has improved the outlook for patients with CRC and shed light on some of the challenges that lie ahead.

OncLive: What are the biggest advancements that have been made in CRC?

Nallapareddy: The biggest developments in CRC have been improvements in OS [of these patients], going from 6 months [traditionally] to patients [now] living up to 4 or 5 years. The new targeted therapies and personalized therapies that we have incorporated into the treatment of CRC [have also helped advance the space].

Could you expand on some of the exciting therapeutic approaches being used?

One of the main therapies we have seen in this arena is immunotherapy, especially in patients with microsatellite instability-high (MSI-H) tumors. We are trying to personalize therapy with the use of targeted therapies, [which is also exciting]. [Of note are] drugs such as cetuximab and bevacizumab, where we are seeing right-sided versus left-sided—directed therapy, which is a more individualized approach being used [based on tumor location].

There are newer therapies such as regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf), and there was the ReDOS trial, in which we introduced regorafenib in a dose-escalated strategy. We do this so that patients can better tolerate the treatment and experience the full benefit of the drug.

How does tumor location impact treatment decisions?

Until recently, we were not very clear on how to decide which treatment options to use for right- versus left-sided tumors. With the CALGB/SWOG 80405 trial, we had data showing that right-sided tumors behave differently from those on the left side of the colon. With these data, we know that patients with left-sided tumors have better OS compared with those with right-sided tumors; this is one thing we have learned [in recent years]. However, we don't know if this is mainly because of the microbiome or due to alterations such as KRAS and BRAF, which are more common in right-sided disease. The prognosis of these patients [is something we do know.]

The second thing [that we learned] is in terms of treatment options. For patients with left-sided tumors, we did see from this study that EGFR-targeted antibodies work better, while VEGF antibodies work better for those with right-sided tumors. In my practice, if I see a patient with right-sided metastatic CRC, I would prefer to use FOLFOX with bevacizumab instead of FOLFOX with cetuximab, even in KRAS wild-type patients. I would do the opposite for left-sided tumors; I would give FOLFOX with cetuximab and likely see a robust response.

What is the current role of immunotherapy in this space?

Immunotherapy is not as robust in CRC as it is in other diseases, such as renal cell carcinoma and melanoma. Although MSI-H tumors account for only about 5% of patients with CRC, the benefit [of this approach] is robust in these patients, and we are seeing better OS and quality of life. The challenge with immunotherapy is figuring out how to incorporate this approach into the microsatellite stable patients and determining if there is a role for immunotherapy or combination immunotherapy in [the majority of patients with] CRC. There are a lot of ongoing trials looking at these "cold tumors," and seeing if we can induce immune response with chemoimmunotherapy. It's exciting to see all of these trials going on, and we are awaiting their results.

You participated in the Peer Exchange portion of tonight’s State of the Science Summit™. What were some of the important topics that were discussed?

One of the interesting topics of discussion had to do with the use of circulating tumor DNA (ctDNA) testing. How do we utilize this testing in CRC, and when is the right time to use it? The question of how to incorporate this into practice is an interesting one. [For example], if patients are getting chemotherapy, would their ctDNA be altered, and as such, would their treatment be altered? We don't know the answers to these questions yet. Currently, ctDNA is being studied in clinical trials, and we are not yet using it in routine practice. I use it mainly in patients in whom I don't have tumor samples available to test for additional [targets].

What would you say is the biggest unanswered question in this space that you hope future research will address?

How do we combine chemotherapy and targeted therapies in more effective ways? We are getting there for patients with KRAS mutations. Also, what are the predictive biomarkers for VEGF inhibitors?

What is your take-home message on the current paradigm in CRC?

CRC has seen huge advancements, and as I said, the OS of these patients is improving. We need to be more patient and see how we can incorporate all of these drugs so that the patients receive the full benefit without much toxicity.

Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1°) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2016;34(suppl 15; abstr 3504). doi: 10.1200/JCO.2016.34.15_suppl.3504.