New therapies, new toxicities

When addressing the emerging toxicities of new anticancer agents – including but not limited to immunotherapy with immune checkpoint inhibitors (ICI), CAR T-cell therapy and bispecific antibodies – we are faced with several challenges. It is critical to gain familiarity with the side-effects of novel agents, but also to be able to stratify mild toxicities from those that are more severe. Secondly, with immunotherapy in particular, the side-effects include autoimmune conditions, cytokine release syndrome and neurotoxicity. These are particularly novel as the mechanisms by which they occur appear distinct from other autoimmune conditions and have given way to a new class of immune-related conditions which could be termed irAE medicine. The ability to diagnose and manage these toxicities is gaining a new skill, in a new area.

The sequence of treatments can impact ongoing patient management and affect future treatment choices. In many clinical trials, patients who have a persistent symptomatic toxicity from a prior treatment may be ineligible for enrolment in a new trial. Certain toxicities may also be synergistic, in that a prior therapy may ‘prime’ the body to develop a future toxicity with subsequent therapy, as has been observed with targeted therapy followed by immunotherapy in patients with EGFR-mutant non-small cell lung cancer (NSCLC). Another example is the use of immunotherapy plus radiotherapy for stage 3 NSCLC, as each treatment is associated with pneumonitis. Certain toxicities exhibit what we call a class effect, in that the toxicities are related to how the agent works and generally, there is a similar spectrum of effects across tumour types and stages. However, there are often certain diseases or disease stages where these toxicities are more common or are of greater concern and they may impact concurrent or sequential treatment.

In clinical practice, patients are usually seen by their oncology teams at every treatment visit, when toxicities are assessed and strategies for their management are implemented. However, certain toxicities may occur at unpredictable timepoints during a patient’s treatment journey and even after treatment cessation. For this reason, patients and oncology teams need to consider the symptoms of novel toxicities both during and after treatment discontinuation, and schedule regular visits as per institutional policies so that these toxicities can be recorded.

In clinical trials, measures of tolerability and quality of life (QoL) should be given equal importance to efficacy outcomes. However, tolerability and QoL outcomes/metrics can be difficult to assess and interpret, while efficacy data are often more quantifiable and therefore more readily understood. To improve the accessibility of data and gain further focus on toxicities, novel means to capture toxicity data are needed, such as time toxicity – the relative burden of treatment on a patient’s time – and patient-reported outcomes.

To optimise the management of novel toxicities, educational initiatives for primary care physicians or GPs are a useful approach given that patients may present to their GPs with these toxicities in the first instance. Furthermore, patient and caregiver education is key to increase awareness of what to expect with treatment and when to call the physician. Educational materials can be delivered in a variety of formats including videos, webinars, apps, in-person meetings and group sessions. Importantly, we need to ensure that they include information on novel agents and how these differ from chemotherapy.