Compared with regorafenib, the combination of the programmed cell death-ligand 1 (PD-L1) inhibitor, atezolizumab, with the MEK inhibitor, cobimetinib, did not improve overall survival (OS) in patients with microsatellite-stable (MSS) chemotherapy-refractory metastatic colorectal cancer (mCRC). The findings from this study were published in Lancet Oncology.1

The availability of effective, safe treatment options for patients with chemotherapy-refractory mCRC represents an area of unmet need. Although durable responses have been achieved in this population of patients with disease characterized by high microsatellite instability (MSI) when treated with immune checkpoint inhibitor therapy, more than 90% of patients with advanced colorectal cancer have MSS disease.

Conversely, little clinical benefit has been observed in clinical studies of immune checkpoint inhibitor therapy in patients with metastatic colorectal cancer classified as MSS.

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While MSS colorectal cancer is generally considered to be immune-excluded in that it lacks T-cell infiltration, preclinical evidence has suggested that inhibition of the mitogen-activated protein kinase (MAPK) pathway may overcome immune resistance in these tumors through upregulation of major histocompatibility complex class I expression, downregulation of cytokines and receptors that interfere with the immune response, and by facilitating infiltration of effector CD8-positive cells into tumor.1 Nevertheless, there is also preclinical evidence of an association between MEK inhibition and impairment of the immune response.2

This multicenter, open-label, phase 3 clinical trial (IMblaze370, ClinicalTrials.gov Identifier: NCT02788279), enrolled adult patients (≥18 years of age) with Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less and chemotherapy-refractory mCRC.

All patients had received treatment with at least 2 prior lines of chemotherapy in the metastatic setting, were stratified by RAS status (using an extended RAS assay that allows for simultaneous detection of multiple mutations in KRAS and NRAS3) and time since diagnosis (ie, >18 months vs ≤18 months), and randomly assigned in a 2:1:1 ratio to receive treatment with the combination of atezolizumab plus cobimetinib, atezolizumab alone, or regorafenib, the standard-of-care in this population of patients.

Of the 363 patients enrolled in the study, 183, 90, and 90 patients received atezolizumab plus cobimetinib, atezolizumab, and regorafenib, respectively. Only approximately 5% of these patients had disease classified as MSI. All study arms were balanced with respect to baseline demographic and clinicopathologic characteristics, including PD-L1 expression and MSS status. Study enrollment was not enriched for patient with tumor characterized by high levels of PD-L1, with approximately 35% to 45% of patients with high PD-L1 tumor levels in each study arm. The primary end point of the study was OS, with progression-free survival, objective response, duration of response, and safety included as secondary end points.

At a median follow-up of 7.3 months, the key finding from this study was the absence of an OS benefit for either the combination of atezolizumab and cobimetinib or single-agent atezolizumab compared with regorafenib, with median OS of 8.87 months, 7.10 months, and 8.51 months for the 3 treatment arms, respectively.

Using regorafenib as a comparator, the hazard ratio for patients in the combination arm was 1.00 (95% CI, 0.73-1.38; P =.99) and 1.19 (95% CI, 0.83-1.71; P =.34) for patients receiving single-agent atezolizumab arm. Subgroup analyses focused on tumor RAS mutation status or level of PD-L1 did not reveal differences in OS according to these biomarkers when patients receiving combination therapy were compared with those receiving regorafenib.1,2

Regarding secondary end points, very few patients achieved an objective response in any of the 3 study arms with rates of 5%, 2%, and 2% (all partial responses) in the combination, single-agent immunotherapy, and regorafenib arms, respectively. Similarly, no significant differences in PFS were observed when the immunotherapy combination arm was compared with regorafenib.

No new safety signals were observed for patients receiving the combination of atezolizumab and cobimetinib. Rates of grade 3/4 adverse events were 61%, 31%, and 58% for patients receiving atezolizumab plus cobimetinib, atezolizumab alone, and regorafenib, respectively. Of these, diarrhea (11%), anemia (6%), increased blood creatine phosphokinase (7%) and fatigue (4%) were the most common all-cause adverse events for patients receiving combination therapy.  Treatment-related deaths included 2 patients in the combination arm, 1 in the regorafenib arm, and none in the single-agent atezolizumab arm. 

Limitations of the study, as noted by the study authors, included the difficult-to-treat patient population, as well as a study design that constrained investigation of treatment efficacy within certain biomarker subgroups.  

“These results highlight the strong biological differences between microsatellite stable

tumors and those with high microsatellite instability, underscoring the divergent treatment needs between these two disease types,” the study authors noted in conclusion.

References

  1. Eng C, Kim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial [published online April 16, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(19)30027-0
  2. Sclafani F. MEK and PD-L1 inhibition in colorectal cancer: a burning blaze turning into a flash in the pan [published online April 16, 2019]. Lancet Oncol. doi: 10.1016/S1470-2045(19)30076-2
  3. Illumina. Extended KRAS panel. https://www.illumina.com/content/dam/illumina-marketing/documents/products/datasheets/praxis-extended-ras-panel-data-sheet-1000000021187.pdf. Accessed May 6, 2019.
  4. Foundation Medicine, Inc. FoundationOne. https://www.foundationmedicineasia.com/home/products/foundationone.html. Accessed May 6, 2019.