The OBR Blog

October 07, 2019 - 10:10 am comments0 Comments

Targeted oral tyrosine kinase inhibitors (TKIs) have an established role in third-line treatment of metastatic colorectal cancer (mCRC), but an expert outlined an entirely new direction of investigation with these drugs at the 2019 European Society of Medical Oncology (ESMO) Congress. The underlying theory that agents within this class might make mCRC susceptible to checkpoint inhibition has finally been given some credibility with positive results in a clinical study.

“This is an incredibly exciting time,” said Heinz Josef Lenz, MD, associate director of clinical research, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles. “There is a feeling that maybe we are unraveling a new option in metastatic CRC with response rates we have not seen in any third line scenarios.”

The story that led to the as-yet unpublished clinical study involves converging progress in understanding how macrophages mediate checkpoint inhibitor resistance and how multikinase inhibitors alter macrophage activity, particularly through effects on colony stimulating factor 1 (CSF-1) receptors. The clinical trial was initiated when regorafenib, which has an established role in mCRC, downregulated tumor-associated macrophages (TAM) in the experimental setting.

“This is looking like a very good strategy to make cold tumors hot,” Dr. Lenz explained.

The principles involved in this approach for converting tumors resistant to immunotherapy to those susceptible might apply across multiple tumor types, but the initial study was conducted in cancers of the gastrointestinal tract. The clinical study that Dr. Lenz found so impressive was recently presented as a poster at the 2019 meeting of the American Society of Clinical Oncology (Fukuoaka S et al. abstract 2522).

In this study, regorafenib and the checkpoint inhibitor nivolumab were evaluated in 25 patients with mCRC and 25 patients with advanced gastric cancer. Patients had a median of three prior lines of treatment. The objective response rate was 38%, a rate in this setting that “has never been seen before,” according to Dr. Lenz.

“Even more impressive, and potentially proving the point that regorafenib is overcoming immunotherapy resistance, three of the responses were observed in patients who had previously failed a checkpoint inhibitor,” Dr. Lenz said.

The potential for targeted therapies to alter the tumor microenvironment in order to enhance T cell infiltration and the anti-tumor efficacy of checkpoint inhibitors has long been appreciated. However, clinical studies until now have been disappointing. Dr. Lenz cited several, including the phase 2 MODUL trial, which found no significant benefit with a combination of atezolizumab and the anti-VEGF drug bevacizumab in mCRC.

Like bevacizumab, regorafenib also inhibits angiogenic activity by targeting VEGF, but a broader range of effects includes inhibition of other growth factors, such as PDGFR and FGFR, as well as oncogenic kinases, such as KIT, RET, and B-RAF. While all of these targets are implicated in an anti-tumor effect, it is the inhibition of the CSF-1 receptor that has become a major focus in the effort to understand its role in immune regulation.

“The CSF-1 axis appears to be important to immune regulation and inhibition, and we are now seeing evidence that activity on this target might be important through its inhibition of tumor associated macrophages,” Dr. Lenz said.

This all adds up to a rationale for the multiple ongoing trials now combining multikinase inhibitors with immune checkpoint inhibitors, including a mCRC study of regorafenib with pembrolizumab that is enrolling patients at Dr. Lenz’s center.

This new direction of study with regorafenib is being initiated just as a dosing optimization scheme has improved its clinical utility. In the pivotal CORRECT trial (Grothey A et al Lancet 2013; 2013:303-312), the overall survival benefit associated with regorafenib in mCRC was accompanied by a challenging rate of initial toxicities. However, a study called ReDOS that was published just weeks prior to the 2019 ESMO Congress has altered its benefit-to-risk ratio.

On the basis of the ReDOS study (Bekaii-Saab et al. Lancet Oncol 2019;20:1070-1082), “we now know how to dose this drug and not compromise quality of life,” said Alex Grothey, MD, Research Institute, Germantown, Tennessee. The principal investigator of CORRECT, Dr. Grothey emphasized that if clinicians have been slow to move to this therapy due to concern about adverse events, the ReDOS study has given regorafenib “a new life.”

In the multicenter ReDOS, 123 mCRC patients were randomized to the standard schedule of 160 mg regorafenib daily for 21 days of a 28-day cycle or to a starting dose of 80 mg/day with weekly 40 mg dose escalations as tolerated to a maximum of 160 mg day. The experimental arm also included one week off therapy in each 28-day cycle. When compared, about twice as many patients in the experimental arm (43% vs. 26%; P=0.04) met the primary endpoint, which was to start a third cycle of therapy.

“On standard dosing, the first cycle was always the most difficult,” said Dr. Grothey, explaining why evaluating a graduated dose made sense. These data are important, because “for a cytotstatic drug like regorafenib, it is the duration of therapy that matters.”

On another front regarding mCRC at the 2019 ESMO Congress, phase 1 results with AMG 510, a TKI targeting the KRAS G12C mutation, proved disappointing despite the promise in tumor models. In 29 patients with mCRC, there was only one partial response. In advanced non-small cell lung cancer (NSCLC) with the KRAS G12C mutation, 11 of 23 patients achieved an objective response, according to data reported from the same study a month ago.

The study did not associate AMB 510 with any dose-limiting toxicities, which was the primary focus of the study. Moreover, the principal investigator, Ramaswamy Govindan, MD, Siteman Cancer Center, Washington University, St. Louis, reported that the data are too limited to rule out clinical activity in mCRC. However, higher rates of response had been expected on the basis of the NSCLC activity, leading several experts to question the viability of the KRAS G12C to be a viable isolated target in mCRC.

by Ted Bosworth

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