With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

Background

There is an immunologic rationale to evaluate immunotherapy in the older glioblastoma population, who have been underrepresented in prior trials. The NUTMEG study evaluated the combination of nivolumab and temozolomide in patients with glioblastoma aged 65 years and older.

Methods

NUTMEG was a multicenter 2:1 randomized phase II trial for patients with newly diagnosed glioblastoma aged 65 years and older. The experimental arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant nivolumab and temozolomide. The standard arm consisted of hypofractionated chemoradiation with temozolomide, then adjuvant temozolomide. The primary objective was to improve overall survival (OS) in the experimental arm.

Results

A total of 103 participants were randomized, with 69 in the experimental arm and 34 in the standard arm. The median (range) age was 73 (65-88) years. After 37 months of follow-up, the median OS was 11.6 months (95% CI, 9.7-13.4) in the experimental arm and 11.8 months (95% CI, 8.3-14.8) in the standard arm. For the experimental arm relative to the standard arm, the OS hazard ratio was 0.85 (95% CI, 0.54-1.33). In the experimental arm, there were three grade 3 immune-related adverse events which resolved, with no unexpected serious adverse events.

Conclusions

Due to insufficient evidence of benefit with nivolumab, the decision was made not to transition to a phase III trial. No new safety signals were identified with nivolumab. This complements the existing series of immunotherapy trials. Research is needed to identify biomarkers and new strategies including combinations.