JCO PO author Dr. Apar K. Ganti shares insights into his JCO PO article, “Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study.” Host Dr. Rafeh Naqash and Dr. Ganti discuss clinical decision-making regarding biopsy; HER2 amplification, mutation, and targeted therapy; drug combinations; and aspects of the TAPUR and DESTINY-Lung studies. Click here to read the article!  

TRANSCRIPT

Dr. Abdul Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Abdul Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the University of Oklahoma Stephenson Cancer Center.

Today we are joined by Dr. Apar Kishor Ganti. Dr. Ganti is a Professor of Medicine and associate director of clinical research at the Fred and Pamela Buffett Cancer Center at the University of Nebraska Medical Center. He's also a staff physician at the VA Nebraska Western Iowa Healthcare System. Dr. Ganti is the lead author of the JCO Precision Oncology article titled "Pertuzumab Plus Trastuzumab in Patients With Lung Cancer With ERBB2 Mutation or Amplification: Results From the Targeted Agent and Profiling Utilization Registry Study," which is also the TAPUR Study.

Dr. Ganti, thank you so much for joining us today.

Dr. Apar Kishor Ganti: Thank you for having me. I'm happy to be here.

Dr. Abdul Rafeh Naqash: For starters, Dr. Ganti, this is one of the trials from the TAPUR Basket study. So I wanted to take this opportunity since this is an ASCO initiative that has been there for a few years now. Could you tell us a little bit of background about the TAPUR initiative, what kind of trials are being run or have been run, and how it all started, basically?

Dr. Apar Kishor Ganti: The TAPUR Study or the Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial which evaluates the anti-tumor activity of commercially available targeted agents in patients with advanced cancers and tumors that have potentially actionable genomic alterations, like mutations, amplifications, etc. And this has multiple arms in multiple malignancies, using drugs that are currently approved in different indications and not necessarily approved for the indication that's being studied. But there's preclinical data that suggests that that particular drug may potentially be active in patients whose tumors harbor those mutations. For example, this present study that we conducted utilized a combination of pertuzumab and trastuzumab, both of which are FDA-approved for the treatment of patients with HER2-positive breast cancers. And we analyzed the efficacy of the combination of these two drugs in patients with lung cancer who had either a HER2 mutation or an amplification of HER2.

Dr. Abdul Rafeh Naqash: Thank you so much for giving us that background. Going to this study specifically, which is one of the very interesting TAPUR studies, what I'm reminded of especially is NCI-MATCH, for example, which runs on a similar premise to this study, where we've seen some successes and some not as exciting combination approach successes that is what we would have wanted to see.

For lung cancer specifically, as you and I both know and perhaps many of the listeners know, there's a lot of actionable drivers that have target therapies that are approved, could you touch on some of those to give a background on where the field currently lies and what are some of the important steps with respect to obtaining next generation sequencing, perhaps in patients. So what your practice is and what you would recommend for these individuals?

Dr. Apar Kishor Ganti: Certainly, non-small cell lung cancer, or non-squamous non-small cell lung cancer, to be more precise, seems to be the poster child for next-generation sequencing. And the importance of NGS testing cannot be overemphasized in these patients. For example, right now we have multiple different drivers that have drugs approved for the management of these patients. The first among them, obviously, was EGFR or epidermal growth factor receptor. And that has been followed fairly successfully by targeting ALK, ROS1, now, more recently, RET, MET, KRAS, and HER2. So if you look at lung adenocarcinomas, almost half of the patients will have a tumor with a mutation that is targetable. And so it's very important to make sure that these patients are tested for, before initiating any therapy. What makes it more important is that the standard of care for patients with non-small cell lung cancer without driver mutations is either immunotherapy or chemoimmunotherapy. And we have found that if a patient has a driver mutation, especially EGFR or ALK, even if their PD-L1 expression is extremely high, their response to checkpoint inhibitors is negligible. And so it is important to make sure that we understand what their molecular status is before starting any treatment in these patients. And I think the key point here is that every patient with advanced non-small cell lung cancer should have next generation sequencing studies done prior to initiation of treatment.

Dr. Abdul Rafeh Naqash: Absolutely. And in your practice, Dr. Ganti, do you tend to do liquid biopsies concurrently when you get a new individual with a diagnosis of lung cancer, or do you do it at some other time point?

Dr. Apar Kishor Ganti: Liquid biopsies, I tend to get them, but not as frequently as some would like. I tend to believe more in tumor biopsies, and I would get liquid biopsies only in the setting where a tumor biopsy is not feasible or if I feel that the patient needs treatment more rapidly than can be expected if I got a tissue biopsy. Liquid biopsies, in my opinion, are good, but they're very dependent on the tumor fraction that is present in the sample that you send. As you very well know, not all patients who have a driver mutation necessarily shed the mutation into the blood. And therefore, even if a patient has a driver mutation in a tumor, there is a small chance that the liquid biopsy may not detect it. So I tend to be more in favor of getting tumor biopsies for next-generation sequencing. In situations where the tumor fraction is high, the concordance between tumor biopsies and liquid biopsies is fairly good.

Dr. Abdul Rafeh Naqash: Thank you so much for that very important clinical decision-making thought process. At least in my practice, when tissue is often the issue, as you very well know, where you don't either have enough tumor cells or the biopsy is just enough to tell you whether it is squamous or non-squamous and not enough for any further sequencing, I try to get liquid biopsies whenever feasible and appropriate so that at least we can rule out some of the driver alterations before I put a patient on immunotherapies, due to the concern for subsequent toxicities if there are driver alterations. But I totally agree, I think tissue is definitely the standard, gold standard. And if you have overlapping mutations in tissue and liquid, then obviously it increases your confidence of treating that individual with that targeted therapy. But in general, tissue definitely, at least we should try to emphasize, and I try to do this often when I get a call from a community oncologist. I'm pretty sure you do the same where we ask for multigene broad gene testing NGS, so that especially when you have HER2 mutations, for example, you won't necessarily capture those as you show on your study here.

Now, going to your study, Dr. Ganti, could you tell us a little bit more about HER2 mutations and amplifications? And there's different levels of evidence where amplification may not lead to expression or expression may not lead to amplification. And then there is a separate category of HER2 mutations. And a lot of what we know for HER2 is from breast cancer. And recently, in the last two to three years now, is for lung cancer also. Could you tell us about how the field is shaping from a HER2 mutational landscape, an amplification landscape, in the lung cancer field?

Dr. Apar Kishor Ganti: As you rightly said, most of our knowledge from HER2 is from the breast cancer world. And frankly, I think we've been spoiled by the data on breast cancer. So, unlike in breast cancer, lung cancer seems to have a much lower frequency of HER2 alterations. And while in breast cancer, HER2 amplification seems to be important and predictive for response to HER2-targeted agents, in lung cancer, we see a combination of mutations and amplifications. So, in a large TCGA study, mutations in HER2 seem to occur in about 2% of all lung cancers. And amplification seems to be occurring in approximately a similar proportion of different patients. So, they seem to be mutually exclusive as best as we can tell.

And, unlike in breast cancer, where HER2 amplification seems to be directly associated with protein over-expression and response to tumor, the data in lung are much less robust. And so, it is not necessarily that an amplification will translate into a prediction of response to a HER2-targeted agent. And we and certain other studies have shown that patients who have HER2 amplification may not respond as well to HER2-targeted therapy as opposed to, for example, patients with HER2 mutations. So, that seems to be the discrepancy in HER2 amplification and HER2 mutations when you look at lung cancer versus breast cancer. And that's another reason why we are doing the TAPUR study at the various arms because what works in one specific cancer with the same mutation or same abnormality may not necessarily work in other cancers.

Dr. Abdul Rafeh Naqash: Absolutely. Thank you for indulging into that side of things. Now, going back to your trial, could you tell us a little bit of background on the eligibility criteria, how you chose some of the different mutations? What were the levels of evidence for some of those mutations from a pathogenicity standpoint, and then what were your endpoints, since this is a clinical trial with a Simon two-stage design?

Dr. Apar Kishor Ganti: Patients who were eligible for the trial included all patients with advanced lung cancer who did not have another FDA-approved treatment or were not candidates for another treatment. They all should have been 18 years or older at the time of diagnosis and have lung cancer with either ERBB2 amplification or we looked at 13 specific mutations, insertions, or deletions, and, if the patient had any of those abnormalities identified by any clear approved next-generation sequencing testing platform, then they would be eligible for the study. We chose these because of how frequently these specific mutations occurred in lung cancer and other cancers. And so, these 13 abnormalities were chosen from the host of HER2 mutations that you can see. Patients should not have received a previous HER2 inhibitor, obviously, and their LV ejection fraction should be normal because of the known risk of decreasing cardiac function with HER2-targeted therapy. They were treated with pertuzumab every three weeks and then combined with trastuzumab. Trastuzumab was given at a loading dose, initially of 8 milligrams per kilogram, and in subsequent cycles, we used 6 milligrams per kilogram. The dose of pertuzumab was a flat dose of 840 milligrams for the first dose and 420 milligrams for subsequent doses.

We continued the treatment till progression or excessive toxicity or patient withdrawal of consent. The endpoints were disease control, which we defined as objective response or stable disease for at least 16 weeks duration. Other endpoints were progression-free survival, overall survival, duration of response, and, of course, safety. We used a Simon two-stage design, as you said. The null hypothesis was that the disease control rate would be 15%, alternative hypothesis was 35%, the power was 85%, alpha was at 10%. So, if in the first stage, less than two out of ten patients had disease control, then the cohort would be closed for futility. If two patients or more had disease control of the first 10, then we expanded to an additional 18 patients for a total study size of 28. So, as far as safety analysis, any patient who received even a single dose of treatment was included in that safety analysis.

Dr. Abdul Rafeh Naqash: Thank you so much for giving us those details about the cohort. Going to the mutation or the amplifications, I'm looking at the cohort, so it seems like more or less, to some extent, there was an equal distribution of the mutations. 50% of individuals had mutations and then around 45%, 43% had amplifications. Did that play into your expectation of how the cohort did in terms of responses or the primary endpoints that you had set? Did you see differences based on those findings of mutations versus amplifications.

Dr. Apar Kishor Ganti: Yes, we did. The disease control rate was 37%, with an overall response rate of 11%. And when you looked at patients who had a partial response, which is three patients, all of them had ERBB2 mutation. And of the patients who had stable disease, only two patients out of seven had an amplification. Five patients had the mutation. So, again, this was similar to what we had expected, that based on previous studies, patients with mutation tend to respond better than patients with alterations.

Dr. Abdul Rafeh Naqash: Definitely. And going to one of the striking figures that you have in this manuscript, of course, you have the waterfall plot, and then you have the swimmer's plot and the spider plot. I'm very intrigued personally by the spider plot, which is the Figure 3 in your paper, especially with this individual that had this long, durable partial response. I believe this was the same individual with the mutation. I believe it was this 776 insertion. Was there anything, any other aspect that could have contributed to this response, or does this mutation, does it have any strong preclinical data of why the activity offer to direct therapy might be more pronounced in this mutation that you came across?

Dr. Apar Kishor Ganti: Not to my knowledge. I don't think we found anything specific or different about this particular patient compared to the others. So, as far as the mutation itself is concerned, it's a fairly common mutation, the G776 insertion. It is one of the most common mutations seen in lung cancer, and studies have shown that patients with the mutation tend to respond. But why this patient responded so long, it's difficult to say. I wish we were able to find out, but unfortunately, we were not able to.

Dr. Abdul Rafeh Naqash: Sure. Another question that I wanted to ask you since this falls into the precision medicine basket study questions. Does TAPUR have a different endpoint for different sub-studies? Because I vaguely remember coming across another paper where I believe a 16-week disease control was also the endpoint. So, is that something universal in TAPUR, or is it specific for specific tumor types and different combination approaches?

Dr. Apar Kishor Ganti: I believe that this is a more generalized feature of the TAPUR study, the stable disease for 16 weeks as a marker of response. Of course, different arms have additional endpoints, but I think this is one of the more common ones.

Dr. Abdul Rafeh Naqash: Now, there has been some work, as you very well pointed out in your paper as well, from others related to HER2 mutations, especially the DESTINY-Lung study. Could you tell us a little bit about that for listeners who may not be well aware of the DESTINY study with trastuzumab deruxtecan targeting the HER2 mutations?

Dr. Apar Kishor Ganti: So, DESTINY-Lung01 was a study of patients with ERBB2 mutated lung cancer. That study just looked at mutation-positive patients as opposed to what we did, looking at both mutation and amplification. And that study showed an overall response rate of 55%, which was much higher and led to the approval of fam- trastuzumab-deruxtecan in this group of patients. And so, one of the differences between our study and trastuzumab deruxtecan DESTINY-Lung01 study, is that our study included patients with both mutations and amplification and our study did not include any cytotoxic drug. And I believe that was one of the big differences, which may make the results of our study intriguing and potentially useful to patients who may not be able to tolerate a cytotoxic agent. Because, as you know, fam-trastuzumab-deruxtecan has the cytotoxic binder. It's an ADC and has been known to have some toxicities. And the thing about lung cancer is that these patients are relatively frail and may not be able to tolerate it. And so, that's one of the major differences, a portion at least for this combination, even though the response rates are much smaller than what we see with fam-trastuzumab-deruxtecan.

Dr. Abdul Rafeh Naqash: And from your practice, have you started using this combination from your study as a potential approach for individuals who may not be candidates for trastuzumab deruxtecan in your clinic?

Dr. Apar Kishor Ganti: I have not as yet because I have not come across a patient who would be eligible for this combination. In my practice, as we have TAPUR open, we have the tucatinib-trastuzumab arm that opened after this arm closed. So my priority is to try and enroll patients onto that cohort. And so I currently have one patient on that. And as you know, this is not a very common alteration, so we don't have as many patients with this. But definitely, this would be a combination that I would put patients on if I felt that they were not a candidate for fam-trastuzumab-deruxtecan.

Dr. Abdul Rafeh Naqash: So, Dr. Ganti, what's the next step after this since your study didn't meet some of its endpoints? What are you planning, or is there a plan to expand on this through the TAPUR mechanism?

Dr. Apar Kishor Ganti: Right now, I don't think that there's a mechanism through TAPUR to expand this particular cohort because there is also another cohort that opened subsequently with tucatinib and trastuzumab. But I think it would not be unreasonable to study this combination in patients who are not candidates for fam-trastuzumab because of the differences in toxicity. So that would be where I would potentially see a role for this particular combination, and I think it should be studied in that setting.

Dr. Abdul Rafeh Naqash: Excellent. Now, I try to dedicate a section of this conversation for provocative discussions that may not be addressed in your paper, but I still like to get insights from experts in the field such as yourself. So comparing it to the NCI-MATCH or some other precision medicine-based initiatives, we do often see that mutations that we think might be driving the process don't necessarily lead to really high or really promising responses to targeted therapies. So in this case, do you think, from a futuristic standpoint, a proteomic-based assay, since I think you work in the proteomic space as well, that would be an interesting way to look at whether signaling actually is altered from a mutation or an amplification, suggesting that that is driving the process, so would be a more attractive target than just looking at a mutational signature?

Dr. Apar Kishor Ganti: I think definitely that should be the way we should be looking at these kinds of studies, because even in this study, even if you look at fam-trastuzumab-deruxtecan and the DESTINY-Lung01 study, we have patients who have definite, identified drivers, and even there, only about half of the patients responded. It was much smaller in our study. But basically what I'm getting at is with the best of the drugs that we have today, only half of our patients respond with HER-2 mutations, for example. So I would definitely favor a more integrated approach to identifying those patients who would be candidates for these targeted agents and not just simply relying on a specific mutation.

Since we are being provocative, I would go one step further and say, “Hey, we have AI. And there are currently AI-based technologies which look at the entire next-generation sequencing profile and try to identify which drugs could potentially be effective in those patients based on a complete understanding of their entire tumor genetic profile, rather than just looking at one or two, or three mutations.” So that, I think, would be a much more robust approach through precision medicine. So, like you just said, that patient that we had who had a prolonged response, we don't know why he or she had a prolonged response. And maybe if we identified a pathway or pathways which were overexpressed or more active in that particular tumor setting, we would be able to identify better targets and better approaches for those patients. So I think that is the way to go in the future.

Dr. Abdul Rafeh Naqash: Excellent. Thanks for indulging into that provocative discussion and hopefully maybe five years down the line when we meet again or run across each other at ASCO, we will say, “Oh, it did actually happen, that multiomics is being used in a way that is suited for the need of the patient.” So matching the right patient to the right therapy at the right time.

So, Dr. Ganti, the last section is going to be dedicated to you as an individual. So you've had a very successful, brilliant career as a clinical trialist and as a lung cancer expert. Tell us, for the sake of our listeners and perhaps some of the early career junior investigators, what your career trajectory has been briefly, and what are some of the things that you felt were successful that could provide advice and insights to people who are earlier in their careers and trying to emulate what perhaps you have done or you are doing?

Dr. Apar Kishor Ganti: Well, that is a big one. I never thought of myself as being a role model for anyone, far less someone who's at the beginning of their career. But what I have always mentioned to students and residents and fellows is basically there is no substitute for hard work. Luck plays some role in this because you need to be at the right place at the right time for some of it, but hard work definitely will pay off. And the other thing that is important is not to get disheartened if your first clinical trial gets rejected or concept gets rejected, or if your first grant gets unscored. That is part of life, and persisting is probably the best way to continue.

Also, continuing to believe in yourself. I've seen a lot of folks, especially once they get into their second or third year after fellowship when things are not going the way they want to, they start to wonder, “Am I suited for this job? Am I the right person? Am I doing this correctly? Should I be doing something else?” And I think it's just a matter of time before they will find success. And also, the other thing is, if one particular approach does not work, there are always other ways that you can look at. So, for example, if you extend a bunch of clinical trial concepts that do not work out, you could potentially look at other ways of answering questions. For example, you could do retrospective analyses, come up with provocative, hypothetical generating questions that could be answered in the future in a prospective study. So there are lots of avenues to do that. And I think I was benefited by my mentors who helped me see this relatively early in my career.

Dr. Abdul Rafeh Naqash: Thank you so much, Dr. Ganti, for all those valuable insights that you've learned over your career and hopefully will help some of the listeners. Before we finish, I'm going to ask you three rapid-fire questions that hopefully will let our listeners--give them a little bit of a sneak peek into you as a person. And you get like five seconds for each question. And they're not complicated questions. My first question to you is what is your favorite food?

Dr. Apar Kishor Ganti: Thai food.

Dr. Abdul Rafeh Naqash: What is your favorite place to go for vacation?

Dr. Apar Kishor Ganti: South Africa.

Dr. Abdul Rafeh Naqash: And what is your favorite hobby?

Dr. Apar Kishor Ganti: Reading.

Dr. Abdul Rafeh Naqash: Well, thank you so much again, Dr. Ganti. This was a very interesting conversation and hopefully, when you or others have other TAPUR-related trial results, perhaps they will again choose JCO PO as a destination for that work.

Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.

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Guest Bio: Dr. Apar Kishor Ganti, MD, MS, is professor of medicine and Associate Director of Clinical Research, Fred & Pamela Buffett Cancer Center at the University of Nebraska Medical Center and Staff Physician at VA Nebraska Western Iowa Health Care System.

Guest COIs:

Apar Kishor Ganti, MD, MS

Consulting or Advisory Role: AstraZeneca, Jazz Pharmaceuticals, Flagship Biosciences, Cardinal Health, Sanofi Genzyme, Regeneron, Eisai

Research Funding: Apexigen (Inst), NEKTAR Pharmaceuticals (Inst), TopAlliance BioSciences Inc (Inst), Novartis (Inst), Iovance (Inst), Mirati Therapeutics (Inst), Chimeric Therapeutics (Inst)

Pertuzumab + Trastuzumab in Lung Cancer with ERBB2 Alterations

JCO Precision Oncology Conversations