Emerging Role of Immune Inhibitors and Predictive Biomarkers: Assignment


Added on  2019-09-16

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The Emerging Role of ImmuneCheckpoint Inhibitors in SCCHN andPredictive Biomarkers

IntroductionThe prevalence of squamous cell carcinoma among all cancersaffecting head and neck region is about 90%. The etiology is mainlyassociated with tobacco and its products, alcohol, virus etc. Early detectionand treatment is associated with a better prognosis. Despite the recentadvances in the treatment modalities, there have been nominalimprovement in the survival rates of the patients in advanced cases. Thetreatment modalities include surgery, radiotherapy, and chemotherapy. Thesuccess rates of the treatment especially in advanced cases have shown onlymarginal improvement. This calls for a quest into newer treatment modalitiesshowing promising results without compromising on the prognosis and thequality of life of the patients. Immunotherapy in Head and Neck CancersThe development of immune checkpoint inhibitors (ICIs) has led to arevolutionary leap in the field of immuno-oncology. Cancer cells escapeimmunosurveillance through different mechanisms, including activation ofimmune checkpoint pathways that suppress antitumor immune responses.ICIs re-activate immune-mediated elimination of cancer cells by blocking theco-inhibitory signaling pathways.HNSCC cancers often express T-cell infiltration due to high mutation burdenand/or viral antigens. The antigens of tumor cells interact with the antigenpresenting cells of the host and results in a cytotoxic response from theactivated T cells. This coupled with the delayed response of memory T cellsproves lethal for the cancer cells. Overtime cancer cells have developedmechanisms to evade the immune system through T cell related pathways.CTLA-4 and PD-1/PD-L1 are the most extensively studied checkpoint inhibitorpathways of the tumor cells. Targeting the programmed cell death-1(PD-1)/PD-L1 pathway has demonstrated clinically meaningful improvement

in both response rate and overall survival in the recurrent and/or metastaticsetting.CheckMate 141 is a randomized phase III study conducted to evaluate theefficacy and safety of nivolumab vs investigator’s choice (IC) of eithermethotrexate, cetuximab or docetaxel, in patients with recurrent and/ormetastatic squamous cell carcinoma of the head and neck (R/M SCCHN) whoexperienced tumor progression or recurrence within 6 months of platinum-based chemotherapy. After a minimum follow-up of 24.2 months’, Nivolumabarm demonstrated significantly longer overall survival (OS) vs theinvestigator’s choice, hazard ratio of 0.68 (95% CI 0.54–0.86). OS benefit wasseen across patients with tumor PD-L1 expression≥1% (HR [95% CI]=0.55[0.39–0.78]) and < 1% (HR [95% CI]=0.73 [0.49–1.09]), and regardless oftumor HPV status. Estimated OS rates at 18, 24, and 30 months withnivolumab were consistent irrespective of PD-L1 expression (< 1%/≥1%). Pembrolizumab, another PD-1 inhibitor, was also tested in a randomizedphase III study, keynote-040, to treat patients with R/M SCCHN whoexperienced tumor progression or recurrence within six months of platinum-based chemotherapy. Pembrolizumab exhibited a clinically meaningfulimprovements in response rates and overall survival but results were notstatistically significant. When looked at patients with PD-L1-high expressions(defined as patients with 50% of tumor proportion score), the magnitude ofbenefit for response rates and overall survival was even more profound andstatistically significant.In phase II HAWK trial, which is another study, was conducted to evaluatedurvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-highpatients (defined as patients with 25% of tumor cells expressing PD-L1) withplatinum-refractory recurrent and/or metastatic HNSCC. Durvalumabdemonstrated objective response rate was 16.2% (95% confidence interval[CI], 9.9-24.4). Median PFS and OS were 2.1 months (95% CI, 1.9-3.7) and7.1 months (95% CI, 4.9-9.9). PFS and OS at 12 months were 14.6% (95% CI,

8.5-22.1) and 33.6% (95% CI, 24.8-42.7). In an ad hoc analysis, HPV-positivepatients had a numerically higher response rate and survival than HPV-negative patients. 29.4% (95% CI, 15.1-47.5) for human papillomavirus(HPV)-positive patients and 10.9% (95% CI, 4.5-21.3) for HPV-negativepatients. Median OS in patients with HPV-positive and HPV-negative tumorswas 10.2 months (95% CI, 7.2-16.3) versus 5.0 months (95% CI, 3.4-8.4),respectively.Combination Immunotherapy (Dual Immune Checkpoint Inhibition)CTL-4 and PD-1Combination checkpoint inhibitors are being studied so as to add asynergistic effect to the co-stimulatory and co-inhibitory action of thebiomarkers. PD-1 can also bind to ligand CD80 which has been shown to bindwith CTLA-4 and regulate its effects on T cells via this ligand. Thus cancertherapies can be targeted towards CTLA-4 and PD-1 are inhibition.Phase III(NCT02741570, Checkmate 651) and Phase III (NCT02551159, KESTREL)have been devoted to this.A randomized, open-label, multicenter phase 2 trial showed that bothdurvalumab plus tremelimumab, and durvalumab monotherapy, hadacceptable safety and efficacy in patients withrecurrent or metastatic headand neck squamous cell carcinoma(R/M HNSCC; ClinicalTrials.govIdentifier:NCT02319044).1The phase 2 trial (CONDOR) were published,inJAMA Oncology. A total of 267 patients were randomly assigned to 1 of 3treatment arms: durvalumab plus tremelimumab, durvalumab monotherapy,or tremelimumab monotherapy. The study reported an objective responserate of 7.8% (95% confidence interval [CI], 3.78-13.79) in the combinationarm, 9.2% (95% CI, 3.46%-19.02%) in the durvalumab arm, and 1.6% (95%CI, 0.04%-8.53%) in the tremelimumab arm. Tumor shrinkage was seen in 40patients (31.0%) in the combination arm, 15 (23.1%) in the durvalumab arm,and 9 (14.3%) in the tremelimumab arm. There were no complete responses

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