Plenary Coverage: ASCO Chief Medical Officer Dr. Richard L. Schilsky Discusses LBA3 with Dr. William Tap.

Welcome to the ASCO Daily News podcast. I'm Dr. Richard Schilsky, senior vice president and chief medical officer of ASCO. I'm pleased to be joined today by Dr. William Tap, a medical oncologist and chief of the sarcoma medical oncology service at Memorial Sloan Kettering Cancer Center. He presented abstract LBA3 at the plenary session reporting results of the ANNOUNCE trial, a randomized placebo controlled double blind phase three trial of doxorubicin plus olaratumab versus doxorubicin plus placebo in patients with advanced soft tissue sarcomas. Dr. Tap, welcome to the podcast. Thank you so much, Dr. Schilsky. I really appreciate the opportunity to talk to you today and also to have had the opportunity to present these data at ASCO during the plenary session.

Olaratumab, a PDGFR alpha antagonist, in combination with doxorubicin was approved by the FDA in 2016 for patients with advanced soft tissue sarcomas who are not candidates for curative radiotherapy or surgery. A phase two trial showed a significant improvement in overall survival for olaratumab plus doxorubicin versus doxorubicin monotherapy. The ANNOUNCE study was designed as a phase three trial to confirm overall survival of this treatment combination. However, the study did not meet its primary endpoint. What are some possible explanations for the difference in outcomes in the phase two and phase three trials?

I think that's such an important question. The results of the ANNOUNCE study have really only become available within the last few months. So therefore, at this time, there is a really large and concerted effort that is ongoing to really understand them, not only as they stand alone, but as you mentioned in the context of the phase 1B two result that led to accelerated approval.

First of all, we have not found any noted discrepancies in study conduct or data integrity which could explain these findings or really discrepancies between the two studies. That's the really important initial fact. There were some notable differences between the two studies. And I know it's not great to compare two studies.

But, for instance, the phase 1B two study was not blinded or did not have a placebo. It had progression free survival as a primary endpoint. There were no subtype specific analyses. And it was a relatively small study, just about 10 sites in the United States. Patients tended to be pretty healthy.

But because it was just a signal finding study, many patients were coming on at later lines in therapy. There was no loading dose in the phase 1B two study. And cardio protectants, because we tended to push higher doses of doxorubicin, were used generally after patients received about 300 milligrams per meter squared.

This is very different when we think about the phase three study, which again was double blinded, placebo controlled with an overall survival primary endpoint. And what's important is that this primary endpoint was a dual primary endpoint that looked at overall survival in the total soft tissue sarcoma population, but also within the leiomyosarcoma population. So we were actually looking within these two populations. And the study could have been positive if we met either of those primary endpoints.

This was a large study, over 110 international sites. And it was rapidly accruing study. So there are some of these differences that are very notable. When we start to think of the differences of why we could have seen the outcomes, the first plausible explanation is that it is possible that olaratumab does not have activity in soft tissue sarcomas. But we would then have to question, why did we see such striking results within the phase 1B two trial. And it's hard to say exactly what that would have been, but it may have been to the small sample size.

As you know, sarcoma really represents 50 to 80 different subtypes. And in the sarcoma community, we now look at these as potentially very different diseases with different biology. So you begin to bring in many different histologies or many different diseases into a clinical trial, and that could also explain some of the results that we saw, as these diseases often have really disparate clinical behavior. The other thing is that with an overall survival endpoint, which is a composite primary endpoint, it is possible that subsequent therapies on the phase two study may have really also affected outcomes when we looked at overall survival. We know there have been a lot of advances in many of the very specific sarcoma subtypes. And this potentially could have affected outcomes or even there could have been some chance in a smaller phase two study.

The other thing that's very possible is that olaratumab has some activity in soft tissue sarcomas in general, but the outcomes were really missed in the phase three study. And this could possibly be again due to the heterogeneity of the study population, not only with the different sarcoma subtypes, as mentioned, but also within sarcoma subtypes. A disease like leiomyosarcoma can actually be a very heterogeneous disease. The other thing, as mentioned before, there could have been some differences in trial design that contributed or how the ANNOUNCE control arm did in this study. So this was not an upfront study, but still for single agent doxorubicin had one of the highest overall survival benefits for doxorubicin alone noted in any phase three clinical trial.

Just to name a few final things, there were a lot of subset analyses that are being done and were done on the phase three study. It did, interestingly, point out two things. One is that patients who had a lower albumin tended to do better with the combination of olaratumab, which suggested the possibility that maybe olaratumab with doxorubicin could work better in sicker patients. And understanding this population in the phase three study seemed to be a healthier patient population in the phase two. That could have affected it.

And there were some very interesting trends when we looked at PDGFR alpha signaling. And this is something that we're very interested in. And although exploratory, we're still looking very closely. But overall, PDGFR alpha positive tumors tended to do worse than PDGFR negative tumors. And there was a very interesting trend noted between PDGFR alpha positive and negative tumors that received olaratumab. There was a six month difference in overall survival noted between these populations favoring PDGFR negative tumors.

So these analyses are still exploratory. And it is uncertain to the prognostic versus predictive significance of these tumors. But it's just a very interesting trend where when we're using a very selective PDGFR alpha inhibitor.

Let me just follow up on that last point, Bill, which seems like a particularly important one. And it's not necessarily intuitive that the biomarker negative population seems to do better. Is it possible that PDGFR alpha is not the actual target for this drug and maybe there's a different target?

We're pretty certain of the specificity of this inhibitor towards PDGFR alpha signaling, because it's a very pure monoclonal antibody. I would wonder more if there is something within mesenchymal biology regarding PDGFR signaling that we may not understand. For example, could targeting PDGFR alpha in tumors that express PDGFR alpha allow for potential up regulation of other aspects of PDGFR signaling or potentially even other signaling pathways?

So one of the difficulties with soft tissue sarcoma is because it's such a heterogeneous disease, again, we may be seeing disparate biology. And because these tumors really fall into mesenchymal malignancies, we still have so much to learn about oncogenesis along mesenchymal cell lineages, and then the interplay with the tumor microenvironment and even the development of metastasis where often PDGFR or other mesenchymal signals really play a role. So where do we go from here? This drug was approved under the FDA accelerated approval pathway, as you said. That requires that post market confirmatory studies be done. The phase three trial didn't confirm the clinical benefit. And now, the sponsor has announced plans to remove the drug from the market. So first of all, what about patients who have been receiving the drug and are benefiting from it? Will they still be able to receive the drug?

So fortunately, they will. As you mentioned, withdrawal is in progress. And that's important for patients and providers to know. And to me, this is the practice changing aspect of this abstract, because olaratumab did gain widespread use in almost over 40 countries.

Because of these data and because we have not yet found any specific reason to explain the data, we are not recommending the initiation of olaratumab with doxorubicin in new patients with soft tissue sarcoma. But as you can imagine, many patients have been on this drug for a long period of time. And many patients and clinicians do believe that the patient is benefiting from the drugs. So this really does require informed conversations with the patient specifically regarding the data of now, and then making the decision if the patient should continue or would like to continue on that drug. And if that's the case, there is a patient access program for continuing patients. There's actually a toll free number, which is 1-833-245-8167, to gain more information about the continued use of the drug as the drug is actually withdrawn from the market. Great. That's really good to know. I'm curious to know what you think this whole experience says about the FDA accelerated approval pathway. Do you think that perhaps this drug was approved too soon?

Well, I think it's a tough question for me to answer, because I'm somewhat biased, very much so regarding the unmet medical need in soft tissue sarcoma. This was the first drug that was technically approved in the upfront setting in soft tissue sarcoma for over 40 years. Normally in sarcoma, we tend to determine efficacy based on few month benefit in progression free survival. So actually having a phase two trial where we saw such tremendous improvements in overall survival for this patient population, in my mind, I think it was very important to give patients access to this drug. The other caveat to this is when we looked at the safety data between doxorubicin and placebo versus doxorubicin and olaratumab, there was very little, if any, difference regarding that safety profile. So olaratumab added very little downside to doxorubicin. So these data and the accelerated approval was really highly debated within the community.

But the drug did gain widespread usage and acceptance. It wasn't unconditional. But many people really started to use the drug. I think the debate was really fueled by a smaller phase two signal, a lack of understanding potentially of the mechanisms of action, which could explain the results that we saw and also the cost, understanding that there was a significant cost with giving this drug to patients.

However, being that we did not have any added toxicity, had the phase three study been positive, I would definitely have liked to allow patients in the two to three year period while we were waiting for the data of the ANNOUNCE study to have access to a potentially life improving drug as opposed to saying, we may have missed a window of a few years to get patients access to this drug. So I think the process, understanding the caveat of the data of the phase two study that I mentioned, could have really worked.

The appropriate phase three study had been designed and was actually completed before FDA approval or accelerated approval was granted. So it was just a matter of waiting for that data. But I do think this is a really important topic to talk about within our community. And I also do think we should consider potentially some ways to mitigate cost for the community while we're waiting for the confirmatory results of the study to mature.

So what else do you see on the horizon for treatment of patients with soft tissue sarcoma? It's clear that there's a high unmet medical need. It's a rare group of patients. As you mentioned, it's a very heterogeneous group of diagnoses and may be difficult to determine the best treatment for this heterogeneous group. Maybe patients need to be sorted. But of course, that's going to make it more challenging to recruit even smaller populations into clinical trials. But as someone who's an expert in the field, where is the field going at this point?

There is a lot of hope. And I think it is still an amazing fertile ground for advancements not only in science, but also in drug development. Sarcomas really represent a major route of oncogenesis in cancer that we know very little about. We know so much more about the hematopoietic malignancies and also about the epithelioid malignancies, but very little about mesenchymal malignancies. And I think what we're seeing is a tremendous growth in our understanding of these tumors, how mesenchymal malignancies interact with tumor microenvironment and metastases. And as you mentioned, we are really beginning to also to genetically dissect out the different sarcoma subtypes. And this is yielding to some very nice advances in very specific sarcoma subtypes.

So I do think as we move forward, we'll continue to see some amazing advances in single sarcoma subtypes. Examples could be diseases like tenosynovial giant cell tumors, PEComas, what we've seen in gastrointestinal stromal tumors, so a lot of hope. I do think the community is really beginning to look at these data from this and other clinical trials to say, how can we better run larger clinical trials maybe in soft tissue sarcoma in general? And is that really the right way? So there is still a tremendous amount of hope to develop drugs for patients. And really finding that right application in the right patient population is going to be critical moving forward. Bill, thanks so much. Again, today, my guest has been Dr. William Tap of Memorial Sloan Kettering Cancer Center. Thank you for being on our podcast today.

Thank you so much.

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