Choices for Advanced Colorectal Cancer Patients with Microsatellite Instability(MSI)--Dr. Marwan G Fakih's Interview at ASCO 2015

Reproduced from Oncology Frontier

Marwan G. Fakih, MD Professor

Arthur & Rosalie Kaplan Chair in Medical Oncology (Interim)

Director, GI Medical Oncology

City of Hope of National Medical Center

Duarte, CA

Oncology Frontier(肿瘤瞭望): As we learned from the NSABP-CO8 study, there is no significant effect on disease-free survival (DFS) or overall survival (OS) when bevacizumab is combined with FOLFOX6 group compared with FOLFOX6 alone group， in stage II or stage III colorectal patients. However, a post hoc analysis of the NSABP-CO8 population by mismatch repair status suggested a benefit from bevacizumab in the mismatch deficient cohort. Could you tell us how do we choose for a stage II/III colorectal patient with defective DNA mismatch repair (dMMR)?

Dr Fakih: We know that patients with stage II and stage III disease can have mismatch repair deficiency. Those patients will usually have microsatellite instability (MSI), more commonly in stage II disease than stage III disease.

About 15-20% of patients with stage II disease will have microsatellite instability while around 10-15% of patients with stage III disease will have microsatellite instability. Historically and as shown in several studies, we know that fluoropyrimidine, either as 5-FU alone or with capecitabine, does not result in any benefit in stage II disease in patients with microsatellite instability. Those patients have an excellent prognosis and they are followed-up with observation and the risk of relapse is very low.

In fact, there are some suggestions that chemotherapy with fluoropyrimidine alone in stage II disease with microsatellite instability may be harmful.

The question is more regarding stage III disease. Those patients have a better prognosis than those without microsatellite instability with what we call a microsatellite stable tumor.

We know from the NSABP study and the MOSAIC clinical trial that these patients do well with chemotherapy. The MOSAIC trial found there is benefit to adding oxaliplatin plus fluoropyrimidine as a FOLFOX backbone in stage III colorectal cancer with MSI is helpful in preventing a relapse.

What the NSABP study has shown further by a post hoc analysis of subgroups is that patients with microsatellite instability who received FOLFOX plus bevacizumab did better than those given FOLFOX.

That is an important finding but we have to remember that this was found in an analysis after the fact and not part of the trial.

So, at best, it is a hypothesis-generating result. I don't think at this point, that it will impact standard of care for patients with microsatellite instability in stage III disease.

At this point, for patients with stage III disease with microsatellite instability, we still recommend those patients receive FOLFOX chemotherapy or oxaliplatin/fluoropyrimidin as standard of care in adjuvant treatment.

Any hypothesis that could explain the favorable trends noted with bevacizumab in tumors with MSI would warrant further investigation. Could you tell us which hypothesis you personally support?

Dr Fakih: It is not very clear why patients with MSI may benefit from bevacizumab.

There is another study called the Quick and Simple and Reliable 2 study (QUASAR2) which looks at capecitabine versus capecitabine plus bevacizumab. An interesting finding of that study is that bevacizumab resulted in harm when added to capecitabine in patients with stage II or III colorectal cancer who did not have microsatellite instability.

Clearly we will not be using bevacizumab in those cases but why it increases the risk of relapse in the QUASAR2 trial is really not very clear. But there are theories as to why patients with microsatellite instability do better with bevacizumab.

We know that VEGF-A，which is blocked by bevacizumab， may have an immunosuppressive function. We know that increased levels of VEGF-A may be associated with increases in Tregs， which are immunosuppressive T-cells. They may also help to reduce the activity of dendritic cells in the tumor. So, in a way, VEGF-A may be an immunosuppressive factor.

We know that microsatellite instability tumors are highly mutated tumors which are associated with a high involvement of T-lymphocytes, which improves the outcomes of patients with these types of tumors. If you suppress these lymphocytes that are already pre-existing in tumors with microsatellite instability with higher levels of VEGF-A, there will be a reduced immune response to the tumor.

So it is very possible that what bevacizumab is doing is giving an extra immune boost to the system by suppressing VEGF-A within the tumor so that the tumor is exposed to an even better immune response than the pre-existing response and therefore reducing the risk of relapse.

The QUASAR2 study did give some signs of improvements in survival for capecitabine plus bevacizumab versus capecitabine alone in that study, but without reaching statistical significance. However, it does parallel what we have seen in the NASBP trial.

Patients with metastatic CRC can benefit from anti-EGFR therapy both in front-line chemotherapy and in downstaging in potentially resectable disease, but patients with CRC in stage II/III respond differently with cetuximab. What do you think is the reason for this disconnect in benefits from anti-EGFR therapy between adjuvant and metastatic disease studies?

Dr Fakih: It is very clear that adding anti-EGFR therapy such as cetuximab to chemotherapy for metastatic colorectal cancer improves the response rate, improves progression-free survival and improves overall survival.

However, we also know, based on two randomized clinical trials in the stage III setting, that adding cetuximab to FOLFOX chemotherapy did not improve response rate. So there is indeed a contradiction of the impact of cetuximab per se on outcomes between metastatic colorectal cancer and patients with stage III disease.

There are different theories as to why that occurs, but there is really no firm conclusion.

One possibility is that while cetuximab increases the response rate， it may not improve the complete pathological response.

If we look at studies where cetuximab is added to FOLFIRI or where anti-EGFR therapy is added to FOLFOX, while that improves the response rate, the incidence of complete pathological response is still very low.

We may not be able to completely eradicate the disease by adding anti-EGFR therapy to chemotherapy. It is also important to know that the tumors are very heterogeneous.

It is possible that anti-EGFR therapy may be effective in differentiating out certain clones of disease that are less important in recurrence but important enough in patients with metastatic disease to induce a response and improve the overall outcomes.

We are seeing this over and over again where something that works in the metastatic setting does not always work in the adjuvant setting.

This has been the case in other agents, such as irinotecan. Adding irinotecan, a cytotoxic chemotherapy, to 5-FU improves response rate, overall survival and progression-free survival in stage IV disease, but does nothing for stage III disease.

That probably has to do with eradication of micrometastatic disease of complete benefit response.

Reproduced from:

[ASCO2015] 转移性结直肠癌的治疗选择——Marwan Fakih教授访谈 2015/5/31 肿瘤瞭望© , 微信公众号