Comment

Certain subsets of patients with multiple myeloma or its precursor conditions are overtreated with current approaches to therapy. Herein, we highlight several key areas where we believe de-escalation of treatment is needed. Dedicated trials to assess these de-escalation approaches and urgent changes to current clinical practices are needed.

In 2023, the US FDA approved several new cancer drugs and biologic agents, including seven small-molecule inhibitors, four bispecific T cell engagers, two anti-PD-1 antibodies and one cell therapy product. Regulatory focus areas included analyses of biomarker-positive subgroups that drive efficacy, equipoise in randomized controlled trials and a new authority to require confirmatory trials be underway before accelerated approval.

The US FDA Accelerated Approval of sotorasib required the sponsor to conduct a randomized trial that compared the safety and efficacy of the approved dose with a lower dose. These results, recently disclosed, have important implications for patients, payers, oncologists and the pharmaceutical industry.

The FDA approval of perioperative pembrolizumab, an approach that combines neoadjuvant and adjuvant therapy with this agent, for patients with early stage non-small-cell lung cancer (NSCLC) contradicts its own stated standard for combination therapies. Given the large population of patients with early stage NSCLC and the high costs of pembrolizumab, whether the adjuvant component provides incremental benefit is an important question.

Through Project Optimus, the FDA calls for radical changes in the design of early phase trials to identify the optimal doses of oncology drugs to achieve maximal efficacy with better tolerability and patient acceptability. Herein, we discuss approaches that will enable the implementation of this initiative as well as some concerns that the draft guidance has raised in the oncology community.

Projected increases of cancer-attributable health-care costs, accompanied by staff shortages, will impose future economic and operational challenges on national health-care systems. Herein, we highlight a series of clinical and health economic rationales in support of publicly funded clinical trial teams that conduct real-world dose-reduction trials aiming for adjustment of cancer drug label doses to reduce not only the financial burden on payers, but also the toxicity burden on patients.

In 2023, a decade after granting Accelerated Approval to the first-in-class BTK inhibitor ibrutinib for the treatment of mantle cell lymphoma, the FDA requested this indication be withdrawn. Herein, we discuss the seemingly inconsistent results from the SHINE and TRIANGLE trials, which relate to the distinct patient populations of these trials, and posit that regulatory approaches should take these nuances into account.

Crossover in a randomized trial can skew the interpretation of the efficacy of a cancer drug. In this Comment, I use examples from clinical trials presented at the 2023 ASCO annual meeting to highlight why ‘allowing’ crossover in randomized trials testing cancer drugs is problematic, and propose that crossovers should either be mandated or prohibited depending on the context.

Telemedicine represents the practical embodiment of patient-centred oncology care, a concept that has become increasingly popular in the past few years. Yet despite the demonstrated benefits of telemedicine, its longitudinal adoption remains limited. Herein we discuss some of the potential challenges that telemedicine faces, as we underutilize this approach relative to its anticipated value.

The FDA Accelerated Approval pathway, which has been pivotal in enabling early access to new oncology drugs over the past three decades, has recently come under increased scrutiny. New draft guidance published in March 2023 offers several possible solutions to improve this pathway, with the ultimate goal of improving outcomes for patients with cancer, but might also have important limitations.

Between 2016 and 2022, 83 previously approved oncology drugs were covered and reimbursed in China through a value-based pricing negotiation programme, which resulted in substantial price cuts but did not improve the correlation between drug cost and clinical benefit. Herein, we call for an improved, transparent value-based pricing model to better account for high-value innovation in oncology drugs.

Transgender patients are a marginalized group for whom current standards of oncology have yet to be optimized. In this Comment, we highlight opportunities for transgender-inclusive and transgender-specific practices across the cancer care continuum and identify evidence gaps that will need to be filled to attain optimal care for transgender populations.

Recent FDA reviews of cemiplimab and sintilimab combined with chemotherapy for patients with advanced-stage non-small-cell lung cancer reached discordant outcomes, as cemiplimab was approved and sintilimab was rejected. The applications share many serious faults, including neither serving an unmet need nor enrolling any patients from the USA. We argue that the FDA criteria should be more transparent and consistent; moreover, the historical policy of the FDA to abstain from consideration of the cost of a drug perpetuates a crisis in oncology care and should be re-examined.

In 2022, the FDA approved numerous new drug and biologic agents, including targeted small molecules, immunotherapeutics, a gene therapy and a radiopharmaceutical. Several drug development challenges were also addressed, and key focus areas for the FDA Oncology Center of Excellence included ongoing monitoring of the Accelerated Approval programme and drug dose optimization.

The development of modern immune-based therapies for multiple myeloma has expanded rapidly over the past several years, and GPRC5D has been identified as a viable immunotherapeutic target. Herein, we discuss data and provide future perspectives on GPRC5D-directed CAR T cells and bispecific antibodies for patients with relapsed and/or refractory multiple myeloma.

The revolution of immunotherapies in oncology has not been matched by the development of companion diagnostic biomarkers able to identify the ideal target populations. Aside from the established pathways for regulatory approval relying on predefined biomarkers, a novel approach based on post hoc biomarker analysis could potentially be instrumental in enhancing the cost-effectiveness of cancer immunotherapy.

Around 100 new cancer drugs, defined as new molecular entities, were approved in China between 2005 and 2021. More than half of these new cancer drugs do not constitute innovations in mechanism of action or therapy and do not have documented meaningful clinical benefit. Approaches are needed to promote meaningful innovation for patients with cancer.

Age is one of the strongest risk factors for cancer and also affects tumour biology, treatment recommendations and response to therapy. Although clinical oncology guidelines advocate against classifying patients on the basis of chronological age alone, most studies and published guidelines use discrete age cutoffs, often heterogeneously. Herein, we discuss age cutoffs from a historical and biological perspective, focusing on breast cancer.

In randomized controlled trials in oncology, changes in quality of life are usually reported together with a description of the differences considered a priori to be clinically important, but overall survival outcomes are rarely provided together with information of what constitutes a clinically meaningful threshold. In this Comment, we propose the benefits that could be derived from reporting overall survival in a similar way to quality of life.

Median overall survival for patients with newly diagnosed multiple myeloma may surpass ten years. Nonetheless, many patients face considerable treatment-related morbidity and relapsed disease. Owing to this typically long overall survival, most multiple myeloma trials now use progression-free survival as their primary end point. In this Comment, we highlight circumstances in which this end point does not best answer the questions that various trials seek to investigate.