Combining immunological and targeted agents in melanoma

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Published: 26 Jun 2014
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Dr Axel Hoos - GlaxoSmithKline, Collegeville, USA

Dr Hoos talks to ecancertv at WIN 2014 about his investigation of immunological and targeted approaches being combined in particular ways to successfully treat metastatic melanoma, with the aim to expand the approach to other cancers.

I was invited to present on a new topic in cancer research which is the combination of immunotherapies with targeted therapies.

What are some of the immunological and targeted approaches being investigated in combination?

As you probably know, GSK Oncology has a large portfolio of targeted agents which we started developing since inception of, actually, the entire oncology unit at GSK. We have brought several new medicines to patients, the latest two, which are a BRAF and a MEK inhibitor named dabrafenib and trametinib, have been widely investigated in melanoma and are now being investigated also in other diseases. We’re aiming to maximise value for patients by combining these now with the emerging new group of immunotherapies.

Why is combining immunological and targeted agents the way forward?

Based on what we know about targeted agents, these have usually high response rates, they have good progression free survival improvements and, in some instances, also survival improvements. But there is often resistance emerging to targeted therapy intervention and the resistance then leads to patients progressing rapidly and succumbing to disease. So our intent here is to offer a more long-term benefit for patients which can be achieved with a new class of cancer immunotherapies. Bringing the two together would actually aim for the best of two worlds: fast response and high response rates with the targeted therapies and a prolonged effect on progression and, ultimately, survival of patients with the immunotherapies. The key points of the talk are primarily the effects of targeted therapies and their main features that would enable them to actually be good candidates for combinations with immunotherapies. One thing that we have aimed to systematically set up at GSK Oncology which is now beginning to be more commonly done in the field at large is the screening of immunological effects for targeted therapies. If you imagine a targeted therapy being designed to actually target the tumour it’s still being given systemically to patients, so it can reach immune cells and it will have effects on immune cells that are usually not understood. So our screening process actually validates the effects of targeted therapies, not just on the tumour but also on the immune system. Having that information will enable us to make decisions about how to combine targeted therapies with immune interventions.

What features make drugs suitable for combination?

They should not be immunosuppressive; they should possibly, in some instances, be immunosupportive or at least modulate the immune system in a way that it synergises with the targeted therapy, with the immunotherapy. Immunotherapy, in most cases, has a well-defined mechanism and the two mechanisms should somewhat come together to have preferably synergistic effects.

Are there any examples of a potentially good drug combination?

We started talking about the BRAF and MEK inhibitors, dabrafenib and trametinib; I spoke about those in my presentation. They have been approved for metastatic melanoma that carries BRAF mutations and we now aim to continue to improve the benefit for patients with this disease by actually adding on immunotherapies to the targeted therapies. There are three trials ongoing right now, one with ipilimumab which is the first marketed cancer immunotherapy for this patient group. We have presented data on this at ASCO and I just presented some of it today. There are two other studies, one with a PD1 inhibitor from Merck and one with a PDL1 inhibitor from MedImmune, both of which we have collaborations for with the two companies. So this is again an effort to be collaborative to bring benefit to patients.

Are the drug combinations you mentioned just being tested in melanoma?

The combinations that I just mentioned are only in melanoma because that’s the disease in which we have the most data and where this step makes the most sense but we can envision doing this in other diseases. So we have recently combined the BRAF and MEK inhibitors with a non-immunotherapy, an EGFR inhibitor called panitumumab, I also referred to that at ASCO and in my talk, and that has shown some good results. So it can be probably carried into other diseases but with immunotherapies we are not yet there.

Drug combinations tend to be tested late in the course of disease, what about using them earlier?

In principle the combination should work early and late. We usually go in with combinations that are more complex after standard therapies that are already approved have failed. So that could be some of the same agents or a different regimen. We will do the phase I study usually in populations with the highest unmet medical need but then at some point might go into early alliance, it depends on the results that you find. Everything we have observed so far actually is looking quite promising. You have to navigate the toxicity of bringing new agents together but you can also see some encouraging activity. So once you put the two together you can then decide into which early alliance this can be carried. We certainly have the intent to make this available to patients as broadly as possible.

Do you foresee a time when immunotherapies will be used earlier in the course of disease?

In melanoma it’s already being widely used. There are new immunotherapies pushing into that space, so the ipilimumab agent was approved in 2011, there are several PD1 or PDL1 inhibitors now being tested and getting close to a regulatory verdict, so where we then might actually have more immunotherapies for melanoma patients. I see them also being investigated in other diseases such as lung cancer, bladder cancer, head and neck cancer and others. So I can see immunotherapies making a greater impact than anybody could have envisioned just a few years back.

What about the safety of using these drugs earlier and what side effects have been seen?

The side effect profile is largely consistent between the early or late alliance but we don’t have large data sets yet in the really early patients so the non-metastatic patients. There was recently a phase III study that tested ipilimumab versus placebo, so monotherapy ipilimumab versus placebo in high risk adjuvant melanoma, the patients have no measurable disease. That was a positive trial with a hazard ratio of 0.75 and a 9 months median PFS improvement. Certainly a positive outcome but the toxicity in that trial was also higher than what has been seen in metastatic patients so it’s something to weigh. It seems that patients that have earlier disease may also have more toxicity but we need to learn more about it. There are not many agents that are in that space yet and there is not enough data to make any clear conclusions.

What research is GSK currently undertaking in relation to your talk?

I mentioned three trials that we’re doing with BRAF and MEK plus immunotherapies in the melanoma setting. So those are the three combination agents ipilimumab, the PD1 inhibitor from Merck and the PDL1 inhibitor from MedImmune. These studies are ongoing, the only study that has data is the ipilimumab combination trial which I presented on today. The other two are still ongoing, there is no data yet that I could have presented. Then there are a variety of other combinations in other diseases. If I give you one more example: in renal cell carcinoma we have Votrient, which is another agent from GSK, a targeted therapy, together with a PD1 inhibitor from Merck. That study is also ongoing but there is not enough data yet to actually present it. There will be other trials that we will conduct with a variety of new agents that can possibly expand the spectrum of therapies we can offer. In general I believe the era of cancer immunotherapy has finally come. It has been a long road, it has been more than thirty years of clinical trials without the desired success. Just in 2011 we really started turning the corner on immunotherapies being really successful, delivering the patient benefit we were looking for. Now we’re learning rapidly how to expand that space and many different companies, but also academic centres, that did not participate in this research before are now on the ball and are working towards making immunotherapies available. So it’s an exciting time and combinations are really part of that story.