O-20 Phase I/IB study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer

Kim, R.; Imanirad, Iman; Carballido, Estrella M.; Strosberg, Jonathan R.; Kim, Y.; Kim, D.

doi:10.1016/j.annonc.2020.04.073

Cited by 11 publications

(13 citation statements)

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“…Although toxicity was similar to the Japanese study REGONIVO, very modest efficacy was reported with no objective responses [122]. Intrinsic genetic differences between the Asian and the Caucasian populations have been suggested as an explanation for these heterogeneous results, though in the absence of a clear functional hypothesis [29].…”

Section: Anti-tams + Immune Checkpoint Inhibitorssupporting

confidence: 55%

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Marmorino

Boccaccino

Germani

et al. 2020

Cancers

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The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.

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Section: Anti-tams + Immune Checkpoint Inhibitorssupporting

confidence: 55%

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Marmorino

Boccaccino

Germani

et al. 2020

Cancers

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“…However, in the phase II REGOMUNE trial (NCT03475953) of regorafenib plus an anti-PD-L1 IgG1 monoclonal antibody, avelumab, in the treatment of solid tumors, including 48 patients with pMMR/MSS mCRC, no objective response was noted, with a median PFS of 3.6 months in mCRC [41]. Furthermore, a phase I/IB trial of regorafenib plus nivolumab in 28 patients with refractory pMMR/MSS CRC showed similar results as the RE-GOMUNE trial, with an ORR of 5% and a median PFS of 4.3 months [42]. Thus, combination treatment with regorafenib and ICIs can result in modest clinical activity in patients with pMMR/MSS CRC.…”

Section: Anti-angiogenetic Inhibitorsmentioning

confidence: 84%

Immunotherapy in Colorectal Cancer: Current and Future Strategies

Ooki

Shinozaki

Yamaguchi

2021

J Anus Rectum Colon

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Despite the recent advances in the systemic treatment of metastatic colorectal cancer (mCRC), prognostic outcomes have remained to be poor. Thus, what is needed is an innovative treatment approach. Immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) have exhibited a durable response and dominated the treatment of various tumor types. However, in mCRC, the clinical benefit is limited in patients with deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H), comprising approximately 5% of mCRC cases, and some do not respond to ICI treatment. Thus, further research is needed to identify predictive biomarkers. The most urgent need is developing effective immunotherapy for patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) cancer, which comprises 95% of mCRC cases. Tumors with the pMMR/MSS phenotype often exhibit a lower tumor mutation burden and fewer tumor-infiltrating lymphocytes than dMMR/MSI-H, leading to immune tolerance and evasion in the tumor microenvironment. Therefore, a number of investigative studies aimed at overcoming tumor resistance in current immunotherapy approaches are underway. A better understanding on the complexity and diversity of the immune system's functioning within the tumor microenvironment will increase the potential for developing predictive biomarkers and novel therapeutic strategies to potentiate anti-tumor immunity in patients with mCRC. In this review, we summarize the most recent advances in immunotherapy based on the findings of pivotal clinical trials for patients with mCRC, highlighting potent therapeutic approaches and predictive biomarkers.

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“…The safety profile of the combination was manageable, and 80 mg was selected as the recommended dose for regorafenib to use in phase II trials. Less promising data have recently been reported by the investigators of a phase I/IB trial conducted in US, where the combination of regorafenib and nivolumab yielded a response rate of 6% and a median PFS of 5.7 months in a population of chemorefractory colorectal cancer patients [13]. These inconsistent results have been largely attributed to the high proportion of patients with unfavourable prognostic features and negative predictive factors for immunotherapy (such as right-sided tumour location and liver metastases).…”

Section: Study Rationalementioning

confidence: 94%

Rationale and design of REGINA, a phase II trial of neoadjuvant regorafenib, nivolumab, and short-course radiotherapy in stage II and III rectal cancer

et al. 2021

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O-20 Phase I/IB study of regorafenib and nivolumab in mismatch repair proficient advanced refractory colorectal cancer

Cited by 11 publications

References 0 publications

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Immunotherapy in Colorectal Cancer: Current and Future Strategies

Rationale and design of REGINA, a phase II trial of neoadjuvant regorafenib, nivolumab, and short-course radiotherapy in stage II and III rectal cancer

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