IO. update on recent approvals for checkpoint inhibitors

June 21, 2019

ASCO hosted a session on FDA approvals and their incorporation into clinical practice- this is a summary of that discussion and the current io landscape.

the IO landscape has been emerging over the last few years, there are now seven FDA approved checkpoint inhibitors in over a dozen different cancer indications [ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab and cemiplimab].

over the last few years researchers and clinicians have better understood the tumour and its immune component and they know there are better outcomes for those patients who have evidence of immune activation.

we are now familiar with the PD-1/PD-L1 interaction and what it really means- these are mechanisms that our normal cells have to protect themselves from autoimmunity, and what really happens is that the tumour cells hijack this as a cloaking mechanism to suppress the immune system. and by blocking PD-1 or PD-L1, it can reactivate the t-cell.

researchers have also come to understand the role that tumour mutational burden plays, and those patients with high tumour mutational burdens are responding to immunotherapy. what we are seeing now is that the majority of approvals happening at the FDA, are for tumours with a high mutational burden like cutaneous squamous cell carcinoma. the more mutations, the higher the objective response rate is, and an indication that the benefit is better for patients.

progression free survival [PFS] in this cohort of patients who are the most symptomatic at progression was also significant. there is some indication of a plateau which is what we see in other solid tumours. as this data matures survival in this population will improve and this is better than what we’ve seen historically.

we now have a therapy that can be added to first-line therapy without the addition of extra toxicities.

with highly immunogenic tumours, like merkel cell carcinoma- pembrolizumab is showing a significant benefit and a high response rate that’s near 50%. and in more granular plots what researchers are showing is rapid response, deep responses, where the majority of patients are getting a solid partial response and the duration that continues and this is in first-line patients. patients can have stability and then move on to a partial response and then continue on to a complete response. so the response can become heightened to a complete response. in merkel cell carcinoma, there’s two types of patients- high mutational load due to UV signature and the viral-positive patients. and this is just evidence that both types respond and do well.

with highly immunogenic tumours, like merkel cell carcinoma- pembrolizumab is showing a significant benefit and a high response rate that’s near 50%. and in more granular plots what researchers are showing is rapid response, deep responses, where the majority of patients are getting a solid partial response and the duration that continues and this is in first-line patients. patients can have stability and then move on to a partial response and then continue on to a complete response. so the response can become heightened to a complete response. in merkel cell carcinoma, there’s two types of patients- high mutational load due to UV signature and the viral-positive patients. and this is just evidence that both types respond and do well.

we can look to add newer checkpoints in these failure patients but there is a need for clinical trials in these populations.

and in cutaneous squamous cell carcinoma which has never had a therapy we now have PD-1 blockage with cemiplimab. and what is being seen a re deep, durable, and rapid responses. approval here is not just in locally advanced unresectable or metastatic. it is also patients who have had multiple surgical procedures and have exhausted radiation, who have a lesion that appears and surgery would not help in any way. and not just responses but clinical benefit that’s durable in patients who go from having partial response to a complete response, even after months of therapy. in primary mediastinal large B-cell lymphomas accelerated approval coming for pembrolizumab- for patients who have failed R-CHOP or others with high response rates, high complete response rates, and partial response rates that are 1/3 of patients. an indication from the melanoma experience is that those patients who get complete response rates, are the ones who stop therapy at two years.

in cervical cancer the fourth leading cause of cancer-related mortality. 98 women, 77% of them positive for PD-L1, with a 14.3% response and a significant duration of response.  responses are under 20%, but they are significant and durable. and just like the breast cancer patients, no PD-L1 staining, probably no response rates. and in patients who previously received standard first-line therapy.

in colorectal cancer approvals  of PD-1s for microsatellite and stable tumours. there is an indication not only of higher response rates but of better benefit in combination ipi | nivo. response rates at 55% in a regimen that’s similar to the renal cell carcinoma regimen. with similar treatment related adverse events.

and finally in melanoma, a recent approval of pembrolizumab looking at randomizing stage IIIa and above provides greater understanding of whether patients benefit by receiving adjuvant PD-1 therapy. while it will take some time to get this answer, it has been approved based on relapse free survival, with a good hazard ratio and is going forward. it has the potential to be a paradigm for every solid tumour where PD-1 is approved.with all these these approvals for multiple solid tumours, there is the possibility now for patients to receive less therapy and more options for patients who have progressed. and moving forward thinking about targeting tumour recognition, activation of immune cells, moving t-cells within the tumour itself versus where we started with single agent PD-1 phase I trials.