Is There a Place for Immunotherapy for Metastatic Microsatellite Stable Colorectal Cancer?

Ghiringhelli, François; Fumet, Jean-David

doi:10.3389/fimmu.2019.01816

Cited by 54 publications

(57 citation statements)

References 97 publications

(99 reference statements)

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“…Based on the above analysis, we can conclude that the combination of nivolumab plus ipilimumab is more effective than nivolumab alone, consistent with previous findings [19,20]. Ghiringhelli et al testified that checkpoint monotherapy inhibitors targeting PD-1 and PD-L1 were not effective in metastatic colorectal cancer patients with microsatellite stable tumors [55]. Neal compared nivolumab plus ipilimumab and nivolumab monotherapy in recurrent SCLC, whereas ORR was higher with nivolumab plus ipilimumab versus nivolumab, toxicities were more common with combination therapy versus nivolumab monotherapy [56].…”

Section: Discussionsupporting

confidence: 87%

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

Chen

Yao

et al. 2020

World J Surg Onc

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Background: Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab plus ipilimumab therapy in cancer treatment. Methods: We examined data from PubMed, Web of Science, EBSCO, and Cochrane Library. Eleven articles fulfilled our criteria, which we divided into 3 groups: nivolumab plus ipilimumab versus nivolumab (the dose used for monotherapy is 3 mg/kg), nivolumab plus ipilimumab versus ipilimumab (the dose used for monotherapy is 3 mg/ kg), and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR), and TRAEs in any grade and grade 3 or higher. Results: The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p < 0.001) and PR (RR: 1.50, p < 0.001) than nivolumab alone. Compared with ipilimumab alone, the combined immunotherapy group had better CR (RR: 4.89, p < 0.001), PR (RR: 2.75, p < 0.001), and ORR (RR: 3.31, p < 0.001). Finally, N1I3 showed better PR (RR: 1.35, p = 0.006) and ORR (RR: 1.21, p = 0.03) than N3I1. The incidence of any TRAEs was similar between both groups (RR: 1.05, p = 0.06). However, the incidence of serious adverse events (grade 3 or higher) was lower in group N3I1 than group N1I3 (RR: 1.51, p < 0.001). Conclusion: This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of nivolumab or ipilimumab monotherapy. In the combined immunotherapy group, N1I3 was more effective than N3I1. Although the side effects were slightly increased in N1I3 group, overall safety was acceptable.

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Section: Discussionsupporting

confidence: 87%

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

Chen

Yao

et al. 2020

World J Surg Onc

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“…As a result, these tumors are highly immunogenic, have high PD‐L1 expression, and consequently exhibit robust cytotoxic T‐cell responses 21 . However, MSS tumors are mostly resistant to anti‐PD‐1 monotherapy because of low mutational burden, immunoexclusion, and immunosuppression 13 . The addition of chemotherapy, antiangiogenic agents, or MEK inhibitors is thought to sensitize MSS tumors to immunotherapy, as these agents potentiate the immune response 14,22 .…”

Section: Discussionmentioning

confidence: 99%

A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite‐stable metastatic colorectal cancer

Patel

Hamada

Makris³

et al. 2021

Cancer Medicine

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Background Microsatellite‐stable (MSS) colorectal cancer (CRC) tends to be poorly immunogenic, with limited treatment options. In MSS CRC xenograft models, trifluridine/tipiracil (FTD/TPI) plus programed death 1 inhibitors resulted in synergistic antitumor activity and increased tumor immunogenicity. This phase 2 study evaluated FTD/TPI plus nivolumab in patients with MSS metastatic CRC. Methods This single‐arm, safety lead‐in study used a Simon's two‐stage design (enrolling 6 patients in the safety lead‐in, proceeding to stage 2 if ≥2 of the first 15 patients achieved a partial or complete response per immune‐related response criteria [irRC] within 6 months). Patients with histologically proven MSS mCRC, and disease progression after ≥2 prior chemotherapy regimens received FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks). Results Between August 2016 and January 2017, 18 patients (50% men; median age 56.5 years) were enrolled; 72% had colon cancer and 56% had KRAS mutations. All patients received treatment (median, 2.5 cycles [range, 1–8]). No dose‐limiting toxicities were observed in the study. The most frequent adverse events (AEs) of any cause and grade were nausea (67%), diarrhea (61%), and neutropenia (50%); 13 patients (72%) experienced grade ≥3 AEs. No patients discontinued treatment because of AEs. No patient achieved a tumor response (either per Response Evaluation Criteria in Solid Tumors [RECIST] or irRC), and the study did not progress to the second stage. Stable disease was achieved in 8 patients per irRC and in 10 patients per RECIST. Median progression‐free survival was 2.2 months (95% CI, 1.8–6.0 months) per irRC and 2.8 months (95% CI, 1.8–5.1 months) per RECIST. Conclusion Patients with refractory MSS metastatic CRC failed to experience clinical benefit with FTD/TPI plus nivolumab, although safety data in this population indicated tolerability and feasibility of this combination. Trial registration number NCT02860546.

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“…Apart from targeted radiosensitization, HSP90 inhibition may also enhance the priming of anti-tumor immune mechanisms that has been observed upon radiotherapy but appears to be restricted to higher single doses and strongly hypofractionated protocols (3 × 8 Gy) (7)(8)(9)(10)(11)42). Improved priming of anti-tumor immune mechanisms would be particularly desirable for patients with high-risk CRC whose tumors are prone to local failure as well as metastasis formation, and who receive radiotherapy in fractions of ≤ 5 Gy -for instance in combination with immunotherapeutic protocols (69)(70)(71). Therefore, the primary motivation for our present study was to examine how HSP90 inhibition enhances radiotherapy-induced immune cell priming with the clinical perspective to develop improved treatment options for high-risk cases of colon cancer.…”

Section: Discussionmentioning

confidence: 99%

Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90

et al. 2020

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Ernst et al. HSP90i Augments Radiotherapy-Induced Immune Priming priming of allogeneic T cell responses in vitro. In summary, HSP90 inhibition-apart from its radiosensitizing potential-obviously enables and supports the initial steps of anti-tumor immune priming upon radiotherapy and thus represents a promising partner for combined modality approaches. The therapeutic performance of such strategies requires further in-depth analyses, especially for but not only limited to CRC.

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Is There a Place for Immunotherapy for Metastatic Microsatellite Stable Colorectal Cancer?

Cited by 54 publications

References 97 publications

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

The efficacy and safety of combined immune checkpoint inhibitors (nivolumab plus ipilimumab): a systematic review and meta-analysis

A phase 2 trial of trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite‐stable metastatic colorectal cancer

Priming of Anti-tumor Immune Mechanisms by Radiotherapy Is Augmented by Inhibition of Heat Shock Protein 90

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