Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses the addition of veliparib to chemotherapy in 

In a recent randomized phase 2 trial, investigators examined the combination of gemcitabine and cisplatin with or without the PARP inhibitor in the frontline treatment of patients with pancreatic ductal adenocarcinomas and a germline 

 mutation, says Mizrahi.Investigators wanted to evaluate whether the addition of a PARP inhibitor to chemotherapy would improve the effectiveness of chemotherapy in this patient population.

Unfortunately, the study showed no benefit with the addition of the PARP inhibitor to the chemotherapy doublet, but patients did have a good overall survival (OS). The median OS for those randomized to the doublet arm was 15.5 months and 16.4 months for those randomized to the triplet arm, which are favorable data for the frontline metastatic setting, says Mizrahi.

 mutations do not inherently have a better prognosis than patients without those mutations. Instead, they do better when they are treated with platinum agents, concludes Mizrahi.

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Jonathan Mizrahi, MD, discusses the addition of veliparib to chemotherapy in BRCA1/2 or PALB2-mutated pancreatic cancer.

Dr. Mizrahi on Addition of PARP Inhibitors to Chemotherapy in Mutated Pancreatic Cancer

Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses efforts being made to target treatment for patients with metastatic colorectal cancer (mCRC).

In terms of looking at targeted agents, it's important to incorporate broad-based molecular profiling to all patients upon diagnosis of mCRC, says Mizrahi. One target that is gaining in popularity in terms of treatment options is HER2. In early-phase studies, patients with HER2 amplifications have been shown to benefit greatly from HER2-targeted therapies, including drugs such as trastuzumab (Herceptin), pertuzumab (Perjeta), or antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1).

There is a lot of area for exploration in patients whose tumors have HER2 amplification. Additionally, for patients with microsatellite instability—high CRC, immunotherapy is moving to the frontline setting. Failing to use this approach in the frontline treatment of this patient population would be a great disservice, concludes Mizrahi.

Jonathan Mizrahi, MD, discusses efforts being made to target treatment for patients with metastatic colorectal cancer.

Dr. Mizrahi on Targeting Treatment in Metastatic Colorectal Cancer

Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses optimal sequencing in patients with 

 V600E-mutant metastatic colorectal cancer (mCRC).

 V600E-mutant mCRC can receive a chemotherapy doublet, such as FOLFOX or FOLFIRI, in the frontline setting, says Mizrahi. Upon progression, the alternate regimen can be used. However, data from the phase III TRIBE2 trial showed that the combination of FOLFOXIRI and bevacizumab (Avastin) led to an improvement in progression-free survival 2 versus sequential use of FOLFOX/bevacizumab and FOLFIRI/bevacizumab in patients with mCRC. In the context of patients with 

-mutant mCRC, who have worse prognosis, Mizrahi recommends using FOLFOXIRI/bevacizumab in the frontline setting.

If the patient progresses on that regimen, the combination of encorafenib (Braftovi) and cetuximab (Erbitux) with or without binimetinib (Mektovi) can be used, adds Mizrahi. The recommendation is based on data from the phase III BEACON CRC trial, which showed an improvement in overall survival (OS) with the doublet and triplet versus irinotecan-based chemotherapy in patients with 

 V600E-mutant mCRC. Because the trial showed equivalent OS data in both of the investigational arms, Mizrahi recommends using the doublet to reduce the toxicity of adding a third drug.

Jonathan Mizrahi, MD, discusses optimal sequencing in patients with BRAF V600E-mutant metastatic colorectal cancer.

Dr. Mizrahi on Optimal Sequencing in BRAF V600E-Mutant mCRC

Jonathan Mizrahi, MD, fellow at The University of Texas MD Anderson Cancer Center, discusses the goal of the phase III COMMIT trial (NCT02997228) in mismatch repair deficient (dMMR) colorectal cancer (CRC).

The ongoing COMMIT trial is evaluating the effectiveness of combination chemotherapy, bevacizumab (Avastin) and/or atezolizumab (Tecentriq) in the treatment of patients with dMMR metastatic CRC. Patients with be randomized 1:1:1 to 3 arms: mFOLFOX6 plus bevacizumab, atezolizumab monotherapy, or mFOLFOX6 plus atezolizumab and bevacizumab, explains Mizrahi.

The goal of the COMMIT trial is to see whether chemotherapy can be omitted altogether for this patient population or whether the addition of immunotherapy to chemotherapy will improve outcomes. Results from this study should provide clarity for how best to treat this patient population, concludes Mizrahi.

Jonathan Mizrahi, MD, discusses the goal of the phase III COMMIT trial in mismatch repair deficient colorectal cancer.

Dr. Mizrahi on the Goal of the COMMIT Trial in dMMR Metastatic CRC

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses encouraging trial findings in metastatic colorectal cancer (mCRC).

A phase II trial presented at the 2019 Gastrointestinal Cancers Symposium evaluated the combination of durvalumab (Imfinzi) and tremelimumab. The study examined PD-L1 inhibition and CTLA-4 inhibition in a refractory patient population. Investigators looked at all-comers and observed an overall survival (OS) benefit, irrespective of PD-L1 status and microsatellite instability-high (MSI-H) status. The OS difference was small but enough to meet the primary endpoint.

Additionally, data were presented on the phase III BEACON CRC study, which is looking at the combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) in patients with 

-mutant metastatic disease. The preliminary results were encouraging, says Mizrahi. In July 2019, the triplet regimen was confirmed to have an OS advantage and to have resulted in a 48% reduction in the risk of progression or death. Due to these findings having exceeded historic data, the combination will likely become the standard of care for these patients, concludes Mizrahi.

Dr. Mizrahi on Encouraging Trial Findings in mCRC

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of early genomic testing in patients with metastatic colorectal cancer (mCRC).

It is crucial to implement genomic testing early in the disease course because doing it later on could cause the patient to miss out on a potentially effective treatment, says Mizrahi. Testing early is always appropriate and is starting to become widely adopted. Unlike dealing with a patient who has oligometastatic disease where cure is still feasible, a patient with mCRC is being treated palliatively.

These are patients who will run through every line of therapy assuming they are fit enough, and as such, they will get to a point where they should be enrolled in a clinical trial. Testing them early, when they are still fit and have a good performance status, is important to inform subsequent therapy decisions, Mizrahi reiterates, adding that it should be done right at diagnosis.

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of early genomic testing in patients with colorectal cancer.

Dr. Mizrahi on the Importance of Early Genomic Testing in CRC

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of personalized care in patients with metastatic colorectal cancer (mCRC).

There is a limited number of cytotoxic chemotherapies that are efficacious for every patient with mCRC. 5-fluorouracil—based regimens with oxaliplatin and irinotecan are effective. Regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) have also shown promise in the refractory setting. Beyond that, personalized therapy is key, Mizrahi says.

Adding biologic agents like anti—EGFR therapy with cetuximab (Erbitux) is a prime example of individualized care. A number of patient factors like tumor sidedness, 

 status, microsatellite instability—high and mismatch repair deficiency can help practitioners make effective treatment decisions.

 also have to be taken into consideration. Once a patient’s mutational status is determined, the optimal combination regimen can be chosen. HER2-targeted therapy is also emerging for the 3% to 4% of patients who have 

 amplification in their tumors. A greater adoption of molecular profiling will help researchers develop more therapies, Mizrahi concludes.

Jonathan Mizrahi, MD, a hematology/oncology fellow at The University of Texas MD Anderson Cancer Center, discusses the importance of personalized care in patients with metastatic colorectal cancer.

Dr. Mizrahi on the Importance of Personalized Care in mCRC

Jonathan Mizrahi, MD, hematology/oncology fellow, The University of Texas MD Anderson Cancer Center, discusses bevacizumab (Avastin) as a chemoprotectant in colorectal cancer (CRC).

In October 2018, Mizrahi and Michael Overman, MD, of The University of Texas MD Anderson Cancer, published a study in 

 on bevacizumab’s ability to reduce oxaliplatin-induced hepatic sinusoidal injury in patients with CRC. The study was done to see if there are certain therapies that, when added to oxaliplatin, could reduce the liver injury caused by oxaliplatin. Hepatic sinusoidal injury is often seen following hepatic resections of metastasectomies, a procedure that is often performed in patients with limited liver metastases, says Mizrahi.

Notably, in patients treated with preoperative bevacizumab and oxaliplatin, the rates of hepatic sinusoidal injury went down. These findings have led physicians to believe that bevacizumab can serve as a protectant against hepatic sinusoidal injury by way of VEGF inhibition and its interaction with reactive oxygen species. Patients who have hepatic sinusoidal injury have increased morbidity after they have liver resection with metastasectomy. If patients can receive bevacizumab preoperatively, the rate of morbidity associated with hepatic sinusoidal injury may decrease.

Jonathan Mizrahi, MD

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