Advances made in the field of immuno-oncology (I-O) in 2015 have greatly expanded our understanding of I-O and added more complexity to its value assessment.
Efficacy beyond salvage therapy and first-line metastatic disease was established in 2015 with the first I-O drug to have an adjuvant indication in its label. The FDA approved an expanded label indication for ipilumimab based on results from EORTC 18071, a randomized, double-blind trial conducted in 951 high-risk patients with stage 3 melanoma who had undergone a complete lymph node dissection. Recurrence-free survival was significantly higher in the ipilimumab group compared with the placebo group at 1 year (63.5% vs 56.1%), at 2 years (51.5% vs 43.8%), and at 3 years (46.5% vs 34.8%). Patients in the ipilimumab group also were 25% less likely to experience melanoma recurrence than those in the placebo group (HR, 0.75; 95% CI, 0.64-0.90; P
= .0013). Median recurrence-free survival was also better in the ipilimumab group (26.1 vs 17.1 months). Forty-nine percent of participants taking ipilimumab had a recurrence after an average of 26 months compared with 62% percent of those receiving a placebo. The analysis of OS data is pending.12I-O versus Targeted Therapy
Whereas efficacy may be measured in the absolute criteria of a clinical trial’s primary endpoints (eg, PFS, OS, etc), value is both more complex and relative as a drug or regimen is assessed in the context of a broad therapeutic arsenal—especially a rapidly expanding arsenal. I-O is not only competing against the standard of care in trial design, but also against other novel therapeutics, the most compelling of which are the growing number of precision/targeted therapies. These new therapeutic classes (I-O and targeted therapies) are being tested against standards of care, with respective head-to-head testing likely years off. However, stakeholder value assessments will not patiently wait for such clinical research. They will more likely use new tools, such as value calculators, to make the cross trial comparisons that health economists have historically refused to validate.
Such comparisons may be done to compare the value of I-O versus targeted therapy in RCC using similarly designed clinical trial results published in 2015.5,13
Nivolumab and cabozantinib (an oral, small-molecule tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor, MET, and AXL) were each compared against everolimus in randomized trials of advanced RCC. OS was longer (25 months vs 19.6 months) and fewer grade 3 or 4 AEs occurred with nivolumab (19%) than with everolimus (37%). PFS was longer with cabozantinib (7.4 months) than with everolimus (3.8 months). The conclusion of an accompanying editorial stated: “Without a significant overall survival benefit and with significant side effects necessitating dose reduction in 60% or more of patients, cabozantinib will not precede nivolumab in the therapeutic sequence.”14Combination Therapy
Researchers are also studying how checkpoint inhibitors can most effectively be used in combination with each other or other cancer therapies. For example, the results of a 2015 study of 945 patients with previously untreated metastatic melanoma showed that nivolumab alone or combined with ipilimumab produced longer PFS than ipilimumab alone.15
For patients with tumors positive for expression of PD-L1, there was no difference in the overall median survival rate for nivolumab or nivolumab and ipilimumab combined. However, among patients with PD-L1–negative tumors, PFS was longer with the combination therapy than with nivolumab alone. Combination therapy will likely extend beyond combining CTLA-4 and PD-1 class drugs.
A boost in the I-O response with enhanced tumor immunogenicity has laid the groundwork for combination trial design. One such observation is that an immunotherapy drug is more likely to be effective in tumors that harbor greater number of mutations. Research suggests that tumors with multiple genetic mutations create more antigens that attract T cells.16
One study determined that 78% of patients with colorectal tumors with mutations of the mismatch repair gene had PFS at 20 weeks after treatment with pembrolizumab compared with only 11% of patients with colorectal tumors without the mutation.7
The theory is that a mutation in the mismatch repair gene results in a greater number of mutations, which itself results in more antigens on the tumor cells that attract T cells. Another study found that patients with NSCLC with high levels of mutations in their tumors linked to smoking were more likely to have a durable clinical response to nivolumab than patients with a low level of mutations in their tumors: 73% compared with 13%.17
Related research suggests the both radiation and chemotherapy may enhance immunotherapy response due to the DNA damage that the treatments cause. This possible relationship has been demonstrated in murine models and has been extended to a variety of clinical trials. Although the standard notion of whole-body radiation therapy is that it is immunosuppressive, there is growing evidence toward the contrary for focal radiation therapy.18
The potential of chemotherapy and radiation therapy to enhance immunogenicity will become an increasing focus of I-O clinical research.Toxicity
The value-based care assessment is a 3-legged stool that cannot stand on efficacy alone, even when efficacy is supported by such compelling biology. Toxicity is the second leg of the stool and warrants increasing attention as our industry shifts philosophically toward a more patient-centered approach to medicine. Although ipilimumab achieved primary endpoints, and was granted FDA label expansion for stage 3 melanoma, the toxicity observed in the trial is noteworthy. The most common side effects reported in this study were rash, diarrhea, fatigue, itching, headache, weight loss, and nausea. AEs led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab, including 182 (39%) during the initial treatment period of 4 doses. In addition, 5 patients (1%) died due to drug-related AEs.12
Such toxicity is also a profound concern for combination trials of CTLA-4 and PD-1 drugs as observed in the melanoma trial—36.4% patients in the combination group, 14.8% in the ipilimumab group, and 7.7% in the nivolumab group dropped out because of adverse drug reactions. One patient in the nivolumab study died from drug-related AEs, as did 1 patient in the ipilimumab group.16
PD-1 and PD-L1 drugs have clearly demonstrated less toxicity, but unique features of their toxicity may still impede adoption. Appropriate provider and patient education of the heretofore uncommon autoimmune complications associated with I-O is prudent, with the following caveats often noted by researchers:
Companion Diagnostics and Cost
AEs associated with checkpoint-blockade immunotherapy can occur during both the treatment phase and after treatment
AEs can present insidiously, but if recognized early, they can be reversed successfully in most cases
Delay in intervention can result in significant morbidity, even mortality
Judicious use of immune suppression appears to be the cornerstone of AE management
Appropriate antibiotic prophylaxis should be considered for patients on long-term immune suppression to prevent opportunistic infections.19
Although both the efficacy and toxicity results are particularly compelling for PD-1 and PD-L1 immunotherapy, cost weighs heavily on the value assessment. I-O treatment courses routinely run in the 6 figures for single agents. Given the less predictable nature of objective bi-dimensional tumor shrinkage as a response criteria, stakeholders responsible for this cost are keenly interested in early identification of nonresponders. Such interest places I-O at the intersection of precision medicine as molecular profiles are sought to differentiate probable responders from likely nonresponders. The level of circulating PD-L1 has been proposed as a molecular target that differentiates potential treatment candidates, and research published in 2015 sheds further light on this important topic.4
Garon et al used immunohistochemical analysis to assess PD-L1 expression in the tumor samples of 495 patients with NSCLC receiving pembrolizumab. Response was assessed every 9 weeks by central review, and results were reported as the percentage of neoplastic cells that stained for membranous PD-L1 (proportion score). In the overall patient population, the ORR was 19.4%, median PFS was 3.7 months, and median OS was 12 months; however, among patients with a proportion score of at least 50%, the ORR was 45.2%, median PFS was 6.3 months, and median OS was not reached at the time of analysis.4
Whether used to differentiate responders from nonresponders, as in Garon’s study or to determine benefit of combined versus monotherapy, as in Larkin’s observations, a confounding observation is that although low PD-L1 expressors may be less likely to respond, those that do respond often have remarkable OS curve tails. One explanation for such results has been the lack of standardization of PD-L1 assays.
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