The Challenges of Immuno-Oncology Combined Clinical Development, Part IV

In the final of a four-part series, Jai Balkissoon, vice president of medical and scientific strategy, writes about the challenges in developing immuno-oncology therapies in combination clinical trials.

From the early phases through to approval, clinical development of immuno-oncology (I-O) combination agents poses significant complexities that can be challenging to address.

Managing immune-related adverse events (IrAE)

As oncologists choose from an expanding array of I-O therapies, we believe tolerability with sustained durable responses will emerge as the key differentiator. I-O treatment can cause unique immune reactions in any tissue or organ system.

Treatment with both CTLA-4 and PD-1/PD-L1 blockade has been associated with immune-related adverse events (IrAEs). PD-1/PD-L1 blockade is associated with fewer IrAEs as compared to CTLA-4 blockade. Although significant clinical benefits are apparent, increased toxicity with the combination of nivolumab and ipilimumab has been seen in patients with advanced melanoma resulting in the investigation of additional dosing regimens. Other important toxicities that are relevant to immunotherapy include cytokine release syndrome (CRS) that is commonly seen with CAR T-cell therapy. This syndrome can be fatal if not anticipated and managed properly.

Immune-related response criteria

Occasionally, unusual kinetics of tumor response can be seen with progression of target lesions or development of new lesions with responses seen in the next tumor assessment. Target lesions may appear to increase in size with treatment. This delayed clinical response is occasionally seen in patients receiving checkpoint blockade, most commonly in patients with metastatic melanoma. Site staff must be properly trained in iRECIST to respond appropriately to avoid premature stoppage of treatment. It’s also important to educate patients to report symptoms early so appropriate management can occur without discontinuing treatment.

The I-O field has advanced to better elucidate the tumor/immune microenvironment, which is unlocking new and expanding therapies, indications and combinations, while transforming cancer care. With patients and clinicians clamoring to gain access to new I-O regimens faster, the race is on to identify effective and tolerable immunotherapies in both solid tumors and hematologic malignancies, generate high-quality data, accelerate approvals and ensure patient safety.

Advancing immuno-oncology therapies in clinical trials

We expect to see a surge of innovations that will help propel the development of the I-O landscape. This innovation will come on a diverse range of fronts. To name a few, we anticipate a deepening understanding and application of biomarkers, the adoption of JiT activation models that connect studies to patients within their own local communities, more patient centric studies that leverage unique trial designs and new approaches to address the important issues of financial toxicity and patient access.

Jai Balkissoon is a vice president of medical and scientific strategy. Read part one, part two and part three of this series. Or read the white paper “Addressing key challenges in the clinical development of combination immuno-oncology therapies: A CRO’s perspective.”