Roche Halts Colorectal Cancer Trial Recruitment After 4 Patient Deaths

Roche announced it had temporarily halted recruiting patients to its Phase II MODUL clinical trial for metastatic colorectal cancer after four patient deaths. The patients were receiving Tecentriq (atezolizumab) in combination with Exelixis ’ MEK inhibitor Cotellic (cobimetinib).

One death was for treatment-related cardiogenic shock. Two of the deaths were because of disease progression. The fourth patient was apparently not related to treatment. The companies have emphasized that they are only stopping recruitment to evaluate the data, not halting the trial itself.

The trial is studying combinations of drugs as maintenance treatment of first-line metastatic colorectal cancer (mCRC) in biomarker-selected populations after induction treatment with FOLFOX chemotherapy and Genentech’s Avastin (bevacizumab). The specific cohort was evaluating Tecentriq plus Cotellic for HER2-negative, microsatellite instability-high (MSI-H) patients, HER2-negative, microsatellite-stable, wild-type BRAF patients, and HER2-negative, microsatellite-stable, BRAF-mutant, K-Ras (KRAS)-mutant patients.

Otherwise, no new safety issues were observed. The company also indicated that the decision to temporarily halt recruitment for this trial will not affects other clinical trials ongoing for the combo treatment, including a Phase III IMblaze370 trial as third-line treatment of mCRC. Top-line results from the IMblaze370 trial are expected before mid-year.

Tecentriq is a humanized monoclonal antibody against PD-L1. It is approved in the U.S. and Europe to treat metastatic non-small cell lung cancer (NSCLC) in patients whose disease has progressed during or after platinum-containing chemotherapy, in addition to locally advanced or metastatic urothelial carcinoma.

Cotellic, marketed by Exelixis and Genentech, a Roche company, has been approved to treat unresectable or metastatic melanoma in combination with Zelboraf (vemurafenib) in patients with the BRAF V600E or V600K mutation.

Roche stated, "The IDMC recommendation followed an observed imbalance in the number of deaths in the experimental arm versus the control arm. At the time of the IDMC review, three deaths occurred on the experimental arm. One death due to cardiogenic shock was treatment related, while the other two deaths were due to disease progression. We recently learned of another death in the Cohort 4 experimental arm, which was documented as not related to study treatment. We are proactively providing the latest information on all the cases to the IDMC."

Roche stock appears unaffected by the news. Exelixis, which had been on a downward trajectory since February, took a hit, but appears to be recovering. Kennen MacKay, an analyst with RBC, said in a note to clients, "Our correspondence with Exelixis management highlights that this is a temporary halt on recruitment only, which could enable the (data monitoring committee) to address questions." In light of that, MacKay urged investors to buy at the dip.

MacKay went on to say, "We see (Monday’s) Exelixis weakness on this trial halt amplified by increased investor skepticism/concern toward immuno-oncology following Incyte’s Echo-301 epacadostat plus Keytruda failure."

This refers to news on April 6 that Merck & Co. and Incyte Corporation’s Phase III ECHO-301/KEYNOTE-252 trial evaluating epacadostat in combination with Merck’s Keytruda in unresectable or metastatic melanoma failed to meet the primary endpoint of progression-free survival. The second primary endpoint of overall survival is also not expected to hit statistical significance. As a result, the companies have halted that trial.

This trial appears to be raising overall concerns among investors about the validity of the combination treatments. Bloomberg noted, "Adding drugs that supercharge the immune system differently could expand the reach of PD-1/L1’s and increase sales by billions of dollars. Incyte’s failure is a blow to that idea, or at the very least to the way it is being pursued. Epacadostat flopped when used as a solo treatment, but it attracted a lot of hype based on very early combination results. Merck and several competitors have dived headfirst into additional expensive R&D. At least 30 active trials are underway with Incyte’s drug in different cancers, and additional tests are using other medicines in the same class. At one point last year, analysts projected that epacadostat would generate $3 billion in revenue in 2022. They now expected $600 million, and that’s most likely too optimistic."

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