With the placement of two more checkpoint inhibitor combination trials on partial hold, the US Food and Drug Administration (FDA) has now halted all such trials from four different pharmaceutical companies: Merck, Bristol-Myers Squibb, Celgene, and now Roche. Roche and its subsidiary Genentech announced that the agency has placed a partial hold on two trials that combine atezolizumab (Tecentriq®) with lenalidomide (Revlimid®) or pomalidomide (Pomalyst®) to treat relapsed/refractory multiple myeloma.
For those who may have missed the unexpected developments in the trials of checkpoint inhibitors (a type of drug that blocks certain proteins made by immune system cells, enabling T-cells to kill cancer cells better) here is a brief recap:
- In July, the FDA placed a clinical hold on three clinical trials using pembrolizumab (Keytruda) following the report of patient deaths in June. Merck said the FDA halted the trials after the data-monitoring committee discovered more patient deaths were observed in the pembrolizumab arm. These trials tested pembrolizumb in combination with lenalidomide and pomalidomide.
- On September 6, Reuters reported that the FDA placed three Bristol-Myers Squibb trials on clinical hold. The trials were using the company’s checkpoint inhibitor nivolumab (Opdivo®) to treat patients with relapsed or refractory multiple myeloma.
- On September 7, Celgene announced that six of its trials (in partnership with AstraZeneca) were placed on full or partial holds by the FDA. Celgene’s trials were using the checkpoint inhibitor durvalumab (Imfinzi) in combination with other immune and chemotherapeutic drugs in blood cancers.
So, what now? The full details of toxicities in Bristol-Myers Squibb’s Keytruda trials have not yet been reviewed publicly, and the other halted studies were very early or not even started, with no toxicities reported. One Asian Myeloma Network trial that included durvalumab (Celgene’s checkpoint inhibitor) was just set to begin. Nonetheless, it is unlikely that further studies can occur without very cautious Phase I retesting, and maybe not even then.
Solving the mysteries of the immune system
This disappointing and sobering story illustrates how much we have to learn about the immune system in myeloma: What is wrong with it? How can it be fine-tuned back to normal, or at least enhanced enough to control myeloma?
The honest answer is that we don't know. Working in the dark, one has to expect problems. In the halted clinical trials, the abnormal immune system is being tweaked without understanding fully how the “normal” one works. Researchers are now working on ways we might tailor immune therapy to increase effectiveness and eliminate toxicities.
A need for optimism
Understandably, there has to be enthusiasm to advance drug development. But the reality is that a lot of luck is involved and there will only be a few home runs. I believe we need to remain optimistic that toxicities will occur only in a subset of patients or that these toxicities may be overcome by changes in dose or schedule or other modification.
In the meantime, all patients involved in any of the affected trials should discuss options with their doctors as soon as possible. We will keep you posted as full details emerge.
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