Rational Immunotherapy Combinations: How’s That Work Again?

I had a very interesting meeting yesterday with a very talented clinical trial physician/researcher and a renowned scientist in the immunotherapy field (I was the dumb tourist, but I’ve played the part before, so no worries). Regardless, the three of us grappled with the question of how to parse the potential immunotherapy combinations that may soon become available, noting that different combinations may prove differentially useful across a wide range of oncology indications.

Lets open the medicine chest and see what target classes are represented (showing just a few examples of each class):

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The perspective of the clinical trial physician/researcher was grounded in the question of what to do with a specific patient – can biomarkers help drive therapy for example. The answer, as we learned at ASCO, is complex. As we heard, biomarkers for PD-1 and PD-L1 are only partly useful, and their use at all may miss patients that would respond despite being negative for the biomarker. This suggests that we will need multiple biomarkers to further subset patients … or that we will need combination therapies to “overrule” the limits PD-1 or PD-L1 biomarkers would impose. The question then becomes which new biomarkers will help us decide which combination of therapies to give to specific patients – and we don’t have this data yet.

The perspective of the immune checkpoint expert was somewhat different and rooted in trying to understand if meshing different biology levers made sense. The obvious one here is pairing inhibitory pathway blockade with immune stimulation, e.g. anti-PD-1 antagonist antibody plus anti-4-1BB agonist antibody. Another approach might be to disable T regulatory cells while boosting T effector cells or targeting myeloid suppressors while stimulating T cells- you can make up your own combinations. The point (and the point of the table) is that this landscape is very complex and it will take time, money, and patients, to sort it out.

The focus on combinations and the need for patients to recruit creates a very dynamic clinical picture. After we saw the compelling data on immunotherapy for NSCLC at ASCO I think it’s fair to say the landscape shifted, and one consequence of this may be that patients who might have been considered for a novel clinical trial therapeutic instead got enrolled into a pembrolizumab cohort (I’m simplifying here, I know). Once pembro was approved for melanoma the landscape shifted again, as physicians, whether clinical trial docs or not, had a novel choice. Quite a lot of ink was spilled (bytes were expended) on whether or not Peregrine Pharmaceuticals (PPHM) for example, would be able to meet its’ clinical trial recruitment timelines in this new landscape (bavituximab is in late stage clinical trials in NSCLC and melanoma). If you listen to the latest earnings call their CEO was asked this very question – are clinical trial enrollments on track – and he very carefully answered that all the sites are activated (which does not answer the question of patient enrollment). It will be very interesting to hear the answer next quarter (I predict it will be positive). Similar questions may soon bedevil other up-and-coming immune checkpoint companies. This begs the question of what data packages new companies will need in their Investigator Brochures in order to attract clinical attention. It’s a critical issue for companies and pipelines.

What about targeted therapeutics, and the combination of these with immune checkpoint therapies? We only know enough to say that the rules have not been established. Small trials and case reports suggest we have to go slowly and test each combo, in each indication, carefully. That’s an awful lot of work yet to be done. In the meantime, the working oncologist, confronted for example with a newly diagnosed NSCLC patient may know that a) the patient carries a known mutation for which there is a targeted drug and b) the patient has a favorable “immune response” profile and has PD-L1+ tumor cells. What to do? We don’t know yet.

There are other consequences in this new landscape. Nearly every oncology vaccine company claims that as soon as they run a combo trial with an anti-PD-1 or anti-CTLA4 antibody their particular vaccine approach will perform beautifully. There are a few problems with this, notably, very few of these companies have a chance in hell of getting an anti-PD-1 antibody via collaboration, and the rest will pay heavily for the privilege. Second we have no idea of how to rationally pair vaccines with immune checkpoint exposure in order to induce optimal responses. Third, there are not enough patients to go around, a simple fact in many indications. So for those investors looking for a renaissance in the oncology vaccine field, I’d say tread carefully.

One way of thinking about this is to ask what a successful combo therapy drug development landscape looks like and happily we don’t have to look far. The hematological malignancies – AML, CML, ALL, NHL, MM etc – have benefitted from having an early bucket of highly efficacious drugs whose tox profile, while perhaps not squeaky clean, is at least well understood. Rituximab (RHHBY, BIIB) is the undisputed leader of the pack here, having been paired in combination with every conceivable therapeutic, followed closely by lenalidomide (CELG) and ibrutinib (JNJ, PCYC). Some combos have worked, some have not, and the whole exercise has taken enormous time and resources, and is ongoing.

Mind you we’ve not touched on the new antibodies, ADCs, bispecifics, CARs, TCRs, TILs and a host of other technologies – it’s just too soon.

In rereading this I realize all I’ve done is ask a bunch of questions: a list of questions I’ll be carrying into the medical conference season as I try to make sense of all the data.

stay tuned.