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Incorporating AKT1 and PIK3CA Pathway Testing and Targeted Therapies in the Management of Advanced Endocrine-Resistant Breast Cancer

Dr. Cristina Saura (Vall d'Hebron University Hospital and VHIO): Hello everyone. It is a pleasure to be here today for this podcast talking about the clinical needs around the PI3K pathway for patients with breast cancer. It is my pleasure to be in this conversation with Dr. Bianchini. Let me start by introducing myself. I am Cristina Saura, a breast medical oncologist working at Vall d'Hebron University Hospital and VHIO in Barcelona, Spain. Dr. Bianchini, please, could you introduce yourself?

Dr. Giampaolo Bianchini (San Raffaele Hospital): I am Giampaolo Bianchini. I am a breast medical oncologist working at San Raffaele Hospital in Milan, Italy.

Dr. Saura: Perhaps we can start talking about where we position this treatment for our patients and when we consider testing the patients for these pathway alterations. Perhaps we can start from there. In your clinical practice, Giampaolo, where do you test your patients? Do you test patients in tumor tissue or in liquid biopsy? And if in tumor tissue, are you using the primary tumor or the metastatic samples?

Dr. Bianchini: That is a very good question, we have adapted over the last year to make a practical approach. So what we decide to do – but I think there are other approaches that can be used – is we test all patients in the first line on the tissue for the biopsy of the metastatic or archival tissue, just to remind you that it is not frequent to acquire an emergent PI3K alteration. So we usually do a test for PI3K, AKT, PTEN, and BRCA mutations. We do a somatic test to do a potential reflex test when we find an alteration in the tissue to eventually confirm if it is germline or not. Then at the time of progression, we do the liquid biopsy, which means we have the possibility to test for ESR1 mutations. Of course, there is also the possibility to capture emergent PI3K or AKT alterations, which cannot be captured initially if they are only captured in the liquid biopsy.

So, what do you do in your practice?

Dr. Saura: As you, we changed our approach based on the data of the INAVO120 trial, because a few years ago, we tested all patients at progression after the first-line setting of CDK4/6 inhibitors because we understood that in that situation, we do not have the option to treat patients upfront with PI3K or AKT inhibitors.

As you, we changed our clinical practice based on the data of the INAVO120 trial with an overall survival benefit to be able to identify those patients upfront that may be PI3K-mutant to discuss with them the opportunity to treat them with PI3K inhibitors with the triplet therapy. And like you, I fully agree that it is important to also test patients at progression of CDK4/6 inhibitors using liquid biopsies to capture the ESR1 mutations, and about 10% of those patients with no available tissue or without mutations at the beginning in the PI3K pathway that may appear as a mechanism of resistance. So, it is a very similar practice in Italy and Spain today.

Based on that, do you have the opportunity to offer your patients inavolisib in the first-line setting, or are you only treating those patients upfront with the triplet in your practice? And if this is the case, which patients are you considering for the triplet upfront?

Dr. Bianchini: I realized in the meantime I was talking that I was strongly influenced by my practice activity. Unfortunately, we are still waiting for the reimbursement of inavolisib in the first line in Italy. That is why I did not mention it, because, of course, in this situation, there is no need just because we do not have the therapeutic opportunity. As soon as we have inavolisib available, to be totally transparent, I will test all patients that could be candidates. So, the only patients that I will exclude are patients with Frank diabetes or with contraindications to start inavolisib, and when clinical judgment makes inavolisib an unsuitable option for me. For the majority of patients, I will say I will test, and I will offer the combination. We are talking about endocrine-resistant patients, so primary and secondary, a population that is hard to treat. And again, for me, the data are really convincing, and I will implement testing in a broader way as soon as the drug becomes available.

Dr. Saura: Yes. Thank you for sharing your experience. You touched upon an important issue, which is the definition or the population that we consider in that space of the first-line setting. In patients with endocrine-resistant, and as you mentioned, we do have the evidence of adding inavolisib as a triplet therapy in combination with palbociclib. 

But you know also that different clinical trials are testing benefit from the triplet in the endocrine-sensitive population. There are ongoing trials recruiting patients with inavolisib and also with the allosteric PI3K inhibitors. We do not have data there. Do you think that we will see the same benefit for those patients with endocrine-sensitive disease, or perhaps it may be enough for those patients to treat them with a doublet and consider PI3K inhibition at progression? We do not have that data, so it is just an opinion.

Dr. Bianchini: No, you provide a really broader view. The PI3K pathway is not just relevant; we now have many options to really target the pathway. We are enrolling in the INAVO123 trial, which is, for instance, exactly offering inavolisib in the endocrine-sensitive population. And now there is also the possibility to use ribociclib, which, in my opinion, is the CDK that I would prefer also for the standard arm.

My expectations are for sure positive. So, we know that PI3K mutations in the metastatic setting, not in the early setting, are associated with poor prognosis. And so, even in the endocrine-sensitive setting, this is a population more in need, and having a target and providing the opportunity to target the triplet – to really target at the same time the endocrine therapy, the CDK inhibitor, and the PI3K pathway – to me is something that is just more than using three drugs; it is really using the synergistic effect that exists among the drugs.

Now, we start to have several PI3K inhibitors in the market and also the results of trials, can you comment about what the future holds, if there is one for alpelisib, that in the past was not just possible to use, but now the VIKTORIA-1 trial, for instance, really is the first trial that provides some evidence of direct comparison? Can you put into context a little bit about the evolution of the opportunity to target the target with an evolving drug?

Dr. Saura: I think that the history of alpelisib has been really unfortunate because in many countries here in Europe – I do not know exactly the situation in Italy, but in Spain – although we had the approval from the European Medicines Agency, we only have the opportunity to treat patients with reimbursement in the public system if patients have not received CDK4/6 inhibitors, which at the end of the day became the standard of care for most of the patients in our clinic. So, really, we have treated a very low percentage of patients with alpelisib. That being said, I think that the pathway started to have more importance because alpelisib had another issue that was very important, which was tolerance. Hyperglycemia and other toxicities like rash really limited the tolerance of patients in the clinic. And I think that the more advanced PI3K/AKT pathway inhibitors are really increasing not only the efficacy results but also tolerance.

Regarding gedatolisib, at ESMO, we have seen the results for the PI3K wild-type population that were impressive at that time. And at ASCO, we have just seen the results for the PI3K-mutant population. And as expected, the median PFS was really impressive in that situation for patients progressing on CDK4/6 inhibitors, with a median PFS around 11 months. I was surprised about the median PFS being very similar for those patients treated with the doublet or the triplet. And I am still willing to see more details on the clinical trial to understand this very similar median PFS, probably related to discontinuations, interruptions, or dose reductions, but this is a detail anyway.

Gedatolisib is an important drug. I think that they will send a file to the FDA for approval. Perhaps the main limitation with gedatolisib are, first, the intravenous administration, because I think that in that space where patients are still endocrine-sensitive and able to be free or far from the hospital, to give them an oral therapy is important. And the second issue is mucositis, which is not grade 3 or higher – most mucositis is grade 1 or 2 – but this may be something that can limit the applicability of this drug in the clinic.

Perhaps you can comment about other PI3Ks that are also in development, the allosteric ones. You know that zovegalisib and tersolisib are PI3K inhibitors that we have data from the Phase I trial, so very limited data, not a lot of patients. But what do you think about the safety and efficacy profile of these two drugs, because both of them have Phase III trials running and recruiting patients?

Dr. Bianchini: Yes, I would like to start a little bit with inavolisib because what really impressed about the INAVO120 trial was the tolerability of inavolisib in a triplet. Just to remind those who are listening, that is a very different situation compared to the triplet use in the VIKTORIA-1 trial, because in the VIKTORIA-1 trial, the treatment was in a post-CDK scenario. In the INAVO120 trial, it was a scenario not exposed to CDK inhibitors, so in some way, palbociclib in that trial was a continuation of a CDK inhibitor. But to come to inavolisib, again, in that trial, it was not a direct comparison with alpelisib, but we were very happy about the overall safety profile. And just to remind you, we have the INAVO121 trial, which is a very clean and similar design to the VIKTORIA-1 trial to test inavolisib plus fulvestrant compared to alpelisib and fulvestrant. We will probably see the results very soon, and I think this is important.

But as you mentioned, there is a new generation of PI3K inhibitors coming that target PI3K at a different site, in a different position of the molecule, with the capability to spare the wild-type PI3K in a manner that is remarkable. So both zovegalisib and tersolisib have a very good safety profile based on the data that are available so far. Some are in posters, some are press releases too, and there is a phase II trial ongoing comparing them to capivasertib. So, the bar is growing, in my opinion, in terms of both the tolerability of the comparison and efficacy. And so, I really like that we are moving from just targeting the pathway to targeting the pathway with a better way to target the target. So, I really like the evolution taking advantage of what we understand about the biology.

What do you think in general about the selection of the PI3K inhibitor when you have a co-mutated patient – an ESR1 and a PIK3CA mutation after a CDK4/6 inhibitor? What you do in your practice?

Dr. Saura: In my clinical practice today, I offer patients the best treatment available at our sites. Most of these options are offered in clinical trials. The ideal scenario is to offer a combination with a SERD plus a PI3K inhibitor, and we do have several clinical trials with different cohorts in Phase I offering that combination. We try to offer those patients these kinds of combinations, sometimes also using CDK2 or CDK4 inhibitors as triplets. So, I think that we are now building the evidence to understand what could be the best option for those patients. We published a meta-analysis led by Guillermo Villacampa, in Cancer Treatment Reviews. We analyzed all the data published with different drugs in that specific scenario that you mentioned, after CDK4/6 inhibitors. Interestingly, we went to this specific population of patients with PIK3CA and ESR1 mutations, and from that meta-analysis, with all the limitations that this work may have, we have seen there that the best options, or the options offering longer median follow-up, was the combination of fulvestrant plus a PI3K inhibitor or a SERD plus a CDK4/6 inhibitor. Nothing new; we have data on these specific scenarios, and I think that this will be the evidence that will be growing in the next few years. I do not know if you have a different approach to these co-mutated patients in your clinic.

Dr. Bianchini: You mentioned the clinical trial, but you are in a big center, a reference center, and you are lucky to have a clinical trial. Thinking about the community in which it is not always possible to offer a clinical trial, I would say my key elements to define are, first, the time on CDK inhibitors in the first line. So, I would never offer elacestrant monotherapy, which is available in Italy, if the progression happened in the first 12 months—with rare exceptions—because we know that in these resistant patients, elacestrant is not effective. Instead, capivasertib, because it is the only – actually, it is an AKT inhibitor, but it targets the PI3K pathway by targeting AKT, which is just below in the pathway to PI3K, is available. I treat these patients where we have actually good results, and also the CAPItello-291 trial, which set the space for capivasertib, demonstrated similar activity in primary and secondary endocrine resistance.

So, for PI3K, there is not as big a separation. For patients that progress after 12 months, usually I look at the burden of disease. If the burden is not huge, I do not have an urgency of response rate; I prefer monotherapy with elacestrant because of the tolerability. I strongly enclose monitoring the patient, with the first CT always at two months, never more than two months, to check if there is a response or not, and eventually, I change. For instance, I can offer AKT. Otherwise, I prefer capivasertib starting and then switching for elacestrant.

A question to you is when in this space do you use ADC or chemotherapy? You do not go for an endocrine option, so which are the guides for you to decide that it is better to go for something else?

Dr. Saura: So we try to treat patients with endocrine therapies. Normally, in combination, as you mentioned, after progression on CDK4/6 inhibitors, the number of patients to whom we may offer monotherapy with a SERD is very limited. The criteria that you shared are the same that we can use here, and we try to continue endocrine therapy-based treatments for all patients who at least had a benefit on the previous line of therapy of more than 6 months, and of course, for those patients that derived benefit for more than 12 months, we really try to find an option of an endocrine therapy-based treatment.

Our threshold or our criteria to move to chemotherapy or ADCs after the first-line setting are definitely endocrine resistance for those patients. So when the progression occurs in less than 6 months is when we consider the option of using ADCs in the clinic. And perhaps with this, I do not know if you use the same criteria in your clinical practice?

Dr. Bianchini: Yes, our approach is really, really very similar, and I think that this is really reasonable for clinical practice. May I suggest you give a few takeaways from the discussion that we have had together?

Dr. Saura: Perhaps the first takeaway could be for our audience to consider when and where to test patients. And as we mentioned before, I think that the primary tumor or the metastatic tumor is a good tissue to test for mutations. At progression on CDK4/6 inhibitors, liquid biopsy seems to be the best way to test patients to capture not only the PIK3CA mutations that may arise but also the ESR1 mutations.

The second takeaway message from me is that targeting the PI3K pathway for patients with luminal disease is really meaningful for those patients. We have now data of an impact on overall survival offering the triplet for those patients upfront. We can consider that option of the triplet upfront or at progression on CDK4/6 inhibitors.

And the third message from my side is that the field is evolving very quickly. We have a plethora of drugs that are giving our patients very good news because efficacy is improving with better drugs like inavolisib, zovegalisib, and tersolisib, with a better safety profile that definitely is improving the quality of life of our patients. Perhaps you want to add something else to these messages, Giampaolo?

Dr. Bianchini: I think you summarized very well. The only thing that I will tell my colleagues is, you know, we in the past considered it enough to decide how to treat metastatic breast cancer because we have ER-positive, HER2 status, and maybe the low or ultra-low status. Now, I think we should enter into the idea that we need to know the PI3K pathway status. It is something that in the metastatic setting we need to know upfront because it is part of our tailoring decision. And if we do this really as a scientific, clinical exercise, we will be able to best use the opportunities coming from enrollment in clinical trials, availability of drugs, and the potential to use them. And just to remind you, the PI3K pathway is not just PI3K; AKT and PTEN are very important – 25% of the alterations in the pathway are related to PTEN and AKT.

And really, I would like to thank Cristina and everyone who was listening. It was really a nice discussion.

Dr. Saura: Thank you.