Recent advances in immuno-oncology and regulatory approvals have been rapid and paradigm shifting in many difficult-to-treat malignancies. Despite immune checkpoint inhibitor therapy becoming the standard of care across multiple tumor types, there are many unanswered questions that need to be addressed before this therapeutic modality can be fully harnessed. Areas of limitations include treatment of patients not sufficiently represented in clinical trials, uncertainty of the optimal treatment dosing and duration, and lack of understanding regarding long-term immune related toxicities and atypical tumor responses. Patients such as those with autoimmune disease, chronic viral infections, limited performance status, and brain metastases were often excluded from initial trials due to concerns of safety. However, limited data suggest that some of these patients can benefit from therapy with manageable toxicities; thus, future studies should incorporate these patients to clearly define safety and efficacy. There are still controversies regarding the optimal dosing strategy that can vary from weight-based to flat dosing, with undefined treatment duration. Further elucidation of the optimal dosing approach and evaluation of predictive biomarkers should be incorporated in the design of future trials. Finally, there are long-term immune-mediated toxicities, atypical tumor responses such as pseudoprogression and endpoints unique to immuno-oncology that are not adequately captured by traditional trial designs; thus, novel study designs are needed. In this article, we discuss in detail the above challenges and propose needed areas of research for exploration and incorporation in the next generation of immuno-oncology clinical trials.

Immunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno-oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era.

Key Points Question What proportion of Medicaid beneficiaries in Kentucky would be included in community engagement (CE) requirements to maintain insurance coverage in the state’s Medicaid demonstration waiver program? Findings In this cross-sectional study, administrative records and survey data collected at the time of the originally intended demonstration waiver implementation date (July 2018) showed that more than 130 000 beneficiaries (40.2% of those included in the demonstration waiver) would likely be required to meet CE requirements. Of this group, approximately 48 000 (14.7% of individuals included in the overall waiver and 36.3% of individuals included in CE requirements) did not meet CE hours at baseline nor were likely to qualify for medical frailty and would have had to take on new activities to maintain benefits. Meaning The findings suggest that most beneficiaries of Medicaid in Kentucky who were included in CE requirements likely already meet required hours or qualify for an exemption for the program.

More than a dozen states have sought federal approval for Section 1115 Medicaid waivers to make premiums and work requirements (ie, requirements to work, volunteer, or engage in education, or caretaking), a condition of Medicaid eligibility for adults deemed able‐bodied. Support for these waivers may differ among adults based on Medicaid participation and political affiliation. We report results from an original 2019 survey of a representative sample of adults in the Commonwealth of Kentucky investigating attitudes regarding work requirements, mandatory premiums, and program exclusions as penalties for noncompliance. We conducted a statewide survey of N = 1203 adults in Kentucky; 601 participants were contacted by phone via random digit dialing and 602 contacted as part of a standing web‐based panel of Kentucky residents. At the time, Kentucky had an approved Section 1115 waiver to establish work requirements and premiums for adults considered able‐bodied. The sample was representative of Kentucky adult population on the basis of age, gender, race/ethnicity, phone use, poverty level, internet access, and geographic region. A majority of Kentuckians (69%) supported the concept of work requirements, agreeing that “If people are able, they should be required to spend time volunteering or working to stay on Medicaid.” Support was higher among nonenrollees (73%) than Medicaid enrollees (64%). But only 43% of the general population, 48% of nonenrollees, and 36% of enrollees agreed that people who do not meet their hours “should lose their Medicaid benefits.” More than half of respondents proposed work hour thresholds that were lower than the 20 hours a week proposed by most states. Among Medicaid enrollees, support for work requirements was higher among those who were employed (versus unemployed), but there was little difference by political party. Opposition to mandatory premiums was high; only 34% of the general population, 38% of nonenrollees, and 28% of enrollees agreed that “People should be required to pay some money out of pocket each month to have Medicaid.” Among people enrolled in Medicaid, support for mandatory premiums was lower among people who were unemployed, and among Democrats compared to Republicans. Only 22% of the general population, 23% of nonenrollees, and 20% of enrollees supported the termination of benefits for people who miss premium payments. The majority of adult Kentucky residents support policies that require Medicaid beneficiaries to work or volunteer. However, a majority also oppose penalties that terminate benefits for people who do not comply. A majority disagreed with mandatory premiums in Medicaid, including program exclusion penalties for premium nonpayment. Work requirements in Medicaid are largely halted due to legal challenges and have been discontinued by executive order in Kentucky. If work requirements and premiums take effect elsewhere, policy makers and researchers should consider how enrollees’ beliefs may affect the acceptability and perceived legitimacy of Medicaid waiver...

Section 1115 demonstration waivers provide a mechanism for states to implement changes to their Medicaid programs. While such waivers are mandated to include evaluations of their impact, randomization – the gold standard for assessing causality – has not typically been a consideration. In a critical departure, the Commonwealth of Kentucky opted to pursue a two-arm randomized controlled trial (RCT) for their controversial 2018 Medicaid Demonstration waiver, which included work requirements as a condition for the subset of beneficiaries deemed able-bodied to maintain eligibility for benefits. Beneficiaries were randomized 9:1 to the new waiver program or a control group who would retain their current benefits as part of the existing Medicaid expansion program. To address potential bias from differential attrition from the Medicaid program that would accrue from solely analyzing administrative data, our team designed a rich, prospective, longitudinal survey to collect primary and secondary outcomes from six categories of interest to policymakers: insurance coverage, health care utilization and quality, health behaviors, socioeconomic measures, personal finances, and health outcomes. At baseline, a subset of survey participants was invited to participate in the collection of biometric samples via in-person follow-up visits, and a cross-section were also invited to participate in qualitative interviews. While the demonstration waiver was terminated before the program began, our study design illustrates that it is possible for other researchers and state agencies seeking to evaluate Medicaid demonstration waivers and other demonstration policies to work together to implement high quality randomized trials – even for controversial policies.