Future of CRC Rests in Greater Genomic Understanding

Marwan Fakih, MD

Several key findings in metastatic colorectal cancer (mCRC) presented at the 2019 Gastrointestinal Cancers Symposium underscored the importance of understanding tumor biology, explained Marwan Fakih, MD.

For example, data from a randomized phase II study demonstrated a prolongation in median overall survival (OS) with the combination of durvalumab (Imfinzi) and tremelimumab plus best supportive care versus supportive care alone in patients with advanced refractory CRC. According to results from the Canadian Cancer Clinical Trials Group CO.26 trial, the immunotherapy regimen resulted in a median OS of 6.6 months when added to best supportive care versus 4.1 months with supportive care alone (HR, 0.72; 90% CI, 0.54-0.97; P = .07).¹

Although results were modest, they suggest that immunotherapy may have a role outside of patients with microsatellite instability—high (MSI-H) tumors, for whom pembrolizumab (Keytruda) is currently indicated after progression on prior therapy.

Moreover, the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) led to an unprecedented improvement in progression-free survival (PFS) and OS in patients with BRAF V600E—mutant mCRC, according to results from the phase III BEACON trial. At a median follow-up of 18.2 months, results indicated a median PFS and OS of 8.0 months and 15.3 months, respectively, with the triplet regimen.²

“The biggest trend in CRC is understanding tumor biology, which is something that is happening across solid tumors,” said Fakih, professor, Department of Medical Oncology and Therapeutics Research, associate director for Clinical Investigations, Comprehensive Cancer Center, medical director, Judy and Bernard Briskin Center for Clinical Research, "We know that the better we understand the biology of the cancer, the better we can characterize CRC and fit our patients with the appropriate treatments.”

OncLive: What were some of the biggest updates from the 2019 Gastrointestinal Cancers Symposium?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Fakih, who is also co-director, Gastrointestinal Cancer Program, and section head, Gastrointestinal Medical Oncology, City of Hope, discussed these trials and highlighted other ongoing research in the field.Fakih: There are 2 main presentations that are important in the research and clinical practice setting of colon cancer. The first study looked at the role of immunotherapy in patients who had progressed on systemic chemotherapy. In this particular phase II trial, patients were randomized to receive a combination of durvalumab and tremelimumab [plus best supportive care] or best supportive care alone. Although we did not see any major responses or significant improvement in PFS in the immunotherapy arm, there was a significant trend in improvement in OS in patients who received the combination. Granted, the improvement was not that clinically significant.

This tells us that patients with mCRC, including those with microsatellite stable (MSS) colon cancer, may have the potential to respond to immunotherapy; this means that CRC is not necessarily a very cold tumor. There may be other strategies that can be investigated to further evaluate immunotherapy and add on to the findings that have been described.

Durvalumab also showed single-agent activity in MSI-H patients. What is the take-home message from that study?

What was the significance of the BEACON trial?

Another important presentation was given by Jérome Galon, PhD, of the INSERM Public Research Institute in France. He provided updates on the diagnostic assay immunoscore and its utility in CRC. The study focused on patients with high-risk stage II disease and interrogated those with a high Immunoscore. If you have a high Immunoscore, it means that the tumor has an immune reaction against it. The patients with clinically "high-risk stage II disease" who had a high Immunoscore had a good prognosis, even without systemic chemotherapy. This tells us that we can certainly think about profiling our patients with stage II disease and high clinical risk by Immunoscore. Then, we can decide which patients should be considered for observation.Durvalumab has also been investigated as a single agent in [patients with] MSI-H CRC. The data from that study are not surprising. We've already had multiple studies that have investigated PD-1 inhibitors, showing that nivolumab (Opdivo) and pembrolizumab monotherapy, as well as combinations of nivolumab plus ipilimumab (Yervoy), are quite effective in patients with MSI-H. It's no surprise that PD-L1 inhibitors result in significant clinical benefits with objective responses and improvements in PFS compared with what we would expect would be no response in MSS colon cancer. [These data] show the power of immunotherapy in MSI-H CRC.The BEACON trial was one of the important highlights of the 2019 Gastrointestinal Cancers Symposium. It’s a phase III clinical trial looking at vertical targeting of the EGFR pathway with the MEK inhibitor binimetinib, the BRAF inhibitor encorafenib, and the EGFR inhibitor cetuximab. Use of the triplet was compared with that of the combination of cetuximab and encorafenib. The triplet was also compared with the combination of cetuximab and irinotecan, which is considered one of the standards of care in second- and third-line treatment of [patients with] RAS wild-type colon cancer.

What are some of the biggest challenges that still need to be addressed in CRC?

You also spoke on regional therapy. Where does that fit into the paradigm?

In the lead-in phase of the study, which evaluated 30 patients, the triplet showed a PFS of 8 months; that is the highest PFS ever reported on a clinical trial in patients with BRAF-mutated colon cancer, irrespective of lines of therapy. Even in the first-line setting, we have not seen a PFS of 8 months. The OS in this highly refractory patient population was quite impressive at 15 months. We are all eagerly awaiting the results from the randomized study. Hopefully these data carry through. If they do, it may become a standard of care in second-line and third-line treatment for patients with BRAF-mutated mCRC.In MSS colon cancer, immunotherapy remains the biggest challenge. We really haven't found the “silver bullet.” It is encouraging to see that durvalumab plus tremelimumab is associated with some improvement, but it’s certainly not sufficient to move into clinical practice. We need to see a better improvement in OS, as well as identify the patients who are going derive a benefit from the combination. We see a trend in improvement in OS, but are there some patients who derive a 4-month improvement in OS? Could we identify a biomarker for those patients? The next questions are going to be, “Why is CRC so resistant to immunotherapy and how we can overcome that? “Is it lymphocytic infiltration? Is it antigen presentation? Is it just a matter of tumor mutation burden? Are there patients who will never benefit from immunotherapy?” All of these are important research questions that need to be addressed.We were all excited about Yttrium-90 radioembolization, but the first-line studies were negative in terms of OS. The benefit with radioembolization for patients with refractory disease is quite limited. Further, only small randomized studies have evaluated that.

Where is the field headed?

At City of Hope, we are looking at hepatic arterial infusion with 5-fluoro-2'-deoxyuridine. We believe there are emerging data that have been published from other centers showing that patients with refractory disease and limited liver metastases derive excellent responses to hepatic arterial infusion. This approach does not affect liver function to the same degree that radioembolization does, and it results in deeper responses. We believe its underutilized as a treatment modality, and we want to increase awareness. We also believe that it requires a very special expertise and should only be done in high volume centers.Besides RAS and BRAF and the impact of sidedness on prognosis and response to anti-EGFR therapy, HER2 targeting has become another area we need to look into. Every patient should be considered for profiling for HER2 amplification. SWOG S1613 is a randomized clinical trial looking at the combination of trastuzumab (Herceptin) and pertuzumab (Perjeta) versus cetuximab and irinotecan, with a crossover design. That study is currently recruiting patients with metastatic CRC and HER2 amplification in the second- and third-line settings. HER2 [amplification] only affects 2% to 3% of patients. However, it is very important to consider HER2-targeting therapy in those patients once they are identified.

Additionally, it’s important to recognize that there is a small portion of patients, even less than those with MSI-H, who may benefit from immunotherapy. For example, the patients with POLE ultra-mutated mCRC. These patients typically have a tumor mutational burden >200 and appear to be quite responsive to immunotherapy.

Fusions are another area of considerable interest. All patients with NTRK fusions do respond to treatment, and there is now an approved therapy for those rare patients. Comprehensive genomic analysis is really a must for every patient with mCRC. We need to profile the tumor to identify the best treatment.

References

1. 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; abstr 481). meetinglibrary.asco.org/record/169381/abstract.
2. 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; abstract 688). doi: 10.1200/JCO.2019.37.4_suppl.688?af=R.