Safety concerns put the brakes on checkpoint inhibitor studies in multiple myeloma

While CAR-T therapy development has regularly been in the spotlight due to an association with lethal adverse events (AEs), immune checkpoint inhibitor therapies, with the exception of some combinations, have so far proved to be comparatively benign.

Severe AEs do occur with current PD-1/PD-L1 antibodies, most commonly with the CTLA-4 antibody ipilimumab (Yervoy®). Immune checkpoint inhibitors act by restoring the immune system’s ability to identify tumours as being “not self”: since the same mechanisms also serve to prevent unwanted immune responses to normal tissue, it’s not surprising that checkpoint inhibitor therapy can result in autoimmune-disease like effects involving the gut, liver, skin and thyroid gland. Severe immune related AEs can require intensive management with steroid and/or other anti-inflammatories, but fortunately occur in a minority of patients.

Studies leading to the approval of checkpoint inhibitors in melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer and bladder cancer progressed without the red flag of safety concerns, so it’s all the more surprising that a slew of multiple myeloma studies involving checkpoint inhibitor combinations have been brought to a halt by the FDA.

Three Merck studies involving anti-PD-L1 (Keytruda®: pembrolizumab) in combination with drugs already used in multiple myeloma treatment (pomalidomide or lenalidomide with dexamethasone) were placed on clinical hold as of early July following a higher number of deaths in the treatment arms. The FDA have since halted enrolment (although not dosing of enrolled subjects in similar studies involving combination with Bristol Myer Squibb’s anti-PD-1 checkpoint inhibitor, Opdivo® (nivolumab) plus either of two antibodies approved for multiple myeloma treatment.

The FDA’s caution also extend to six combination studies sponsored by Celgene, all involving AstraZeneca’s anti-PD-L1 antibody, Infinzi® (durvalumab),with one study being placed on full hold.

Lenalidomide (Revlimid®) and pomalidomide (Pomalyst®), chemical descendant of thalidomide, are approved for the treatment of multiple myeloma.  Lenalidomide and pomalidomide are potent immunomodulators but also act through a variety of other, non-immune mechanisms. It’s tempting to consider excessive up (or down) regulation of cytokines as a likely  smoking gun, but the combination of effects on tumour/immune system interaction with PD-1/PD-L1 may prove hard to unravel.

No approved cancer treatment is effective (or necessarily safe) for all tumour types: clinical experience with checkpoint inhibitors is still at a early stage, so perhaps safety (or efficacy) issues arising with one or more form of malignancy and/or with a number of the various checkpoint inhibitor combinations under study should perhaps not be unexpected and will not derail the advance of immuno-oncology.

The current generation of checkpoint inhibitors might never make for better multiple myeloma treatment but each setback represents an opportunity to gain better insight into what might work, and what’s to be avoided in the ongoing development and deployment of cancer immunotherapy.

Image courtesy of sheelamohan at FreeDigitalPhotos.net

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First flagged in:  UPDATED: Safety fears spur FDA to pause checkpoint combo studies by Bristol-Myers, Celgene. John Carroll. Endpoints News, online 7^th September 2017. http://tinyurl.com/ybekxrzl

Bristol-Myers Squibb Provides an Update on Three Opdivo-based Combination Clinical Studies in Multiple Myeloma. Company press release online 6^th September 2017. http://tinyurl.com/y9wv3h3g

Merck Provides Further Update on Three Multiple Myeloma Studies Evaluating KEYTRUDA® (pembrolizumab) in Combination with Pomalidomide or Lenalidomide. Company press release online 5^th July 2017. http://tinyurl.com/ya9z2tfs