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Jun 8, 2020

Dr. Nathan A. Pennell, associate professor and director of the lung cancer medical oncology program at the Cleveland Clinic Taussig Cancer Institute, shares his insight on the abstracts featured at the #ASCO20 Virtual Scientific Program that show promising advances for patients with lung cancer. Dr. Pennell is also a site investigator in the study by the COVID-19 and Cancer Consortium and discusses the findings of its first report released at #ASCO20.



ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Today I'm speaking with Dr. Nathan Pennell, associate professor and director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute. He is also a consulting editor of JCO Oncology Practice. Dr. Pennell will discuss key abstracts on lung cancer that were featured at the ASCO20 Virtual Scientific Program. He will also tell us about the first report of the COVID-19 and Cancer Consortium that was discussed during the meeting. Dr. Pennell was a site investigator in the study, abstract LBA-110.


Dr. Pennell reports paid consulting for AstraZeneca, Merck, Eli Lilly, Genentech, and Bristol-Myers Squibb. Full disclosure is relating to all Daily News podcasts can be found on our episode pages. Dr. Pennell, it's great to have you on the podcast today.


Dr. Nathan Pennell: Thanks, Geraldine. I'm glad to be able to talk about these abstracts.


ASCO Daily News: So what are the key abstracts that will likely change standard of care in your opinion?


Dr. Nathan Pennell: Well, I think there was one primary abstract that really should change care, although it is not yet involving a drug that's been approved by the FDA at this time. And this was in the plenary session, so this was an abstract number LBA-005, which is the ADAURA study. So this was a phase III randomized trial of the third generation EGFR inhibitor osimertinib, given as adjuvant therapy in people with stage IB or through stage IIIA EGFR mutation positive lung cancer after surgery. Patients who had early stage EGFR mutant cancer were randomly assigned after surgery and adjuvant chemotherapy to up to three years of either osimertinib once a day or a placebo once a day, and the primary endpoint of the study was disease-free survival, with a secondary endpoint of overall survival.


So this trial did fully accrue, and we've been waiting on results. And rather unexpectedly, we recently heard that the trial had been unblinded at an interim analysis, because it had already met its end point for disease-free survival. And they kind of sneaked it into the plenary session, which I thought was really good to be able to get the data out so quickly. So essentially what the study showed was that the primary endpoint, which was disease-free survival in people with either stage II or stage IIIA EGFR mutant lung cancer was significantly longer in people who'd gotten the adjuvant osimertinib versus those who got the placebo.


In fact, at 2 years the disease-free survival was 90% in the treatment group, versus only 44% in the placebo group, with a hazard ratio of 0.17. And a very impressive looking curve. So this was, I think, a very significant finding and one to certainly congratulate the authors for such a meaningful presentation.


The good thing is that it seems to have a big impact on disease-free survival I think the criticism-- so if anyone was following along on social media, you can see there was quite a bit of discussion about this trial-- is that, of course, the most meaningful endpoint in any sort of a curative trial like this is really, does the drug prolong overall survival or does it increase the chance that you're going to be cured of your cancer? And the truth is, because the trial was unblinded so early with only 22 months follow-up, we don't know the answer to that question. In fact, most of the people on the trial were probably still on drug, which has a three-year duration of treatment and it was only 22 months of follow-up.


So we won't know, most likely, for several years, whether overall survival has been impacted by this treatment. However, since the primary endpoint has been met, I think there is a reasonable chance that this will be something that could become available for us. And then we'll have to decide whether to use it.


I think that based upon this magnitude of a difference, I do think this will be practice changing, in that, if it is approved and available for use, it will be offered to patients with resected at least stage II and III EGFR mutant lung cancer.


ASCO Daily News: Dr. Pennell, are there any new agents in development that could potentially change the treatment landscape for patients with lung cancer?


Dr. Nathan Pennell: Well, there are several abstracts that are worth highlighting, I think, in this scenario, two of which actually could change practice. Although I'm not sure that they will. And the reason I say that is that even as the data was being presented in the same month, these drugs became approved by the FDA, and so therefore are ones that we can discuss about using.


So the two abstracts I want to discuss first are 9500 and 9501, which were the CheckMate trials of nivolumab and ipilimumab versus chemotherapy in advanced non-small-cell lung cancer. The first trial was an update on the phase III CheckMate-227 study comparing nivolumab and ipilimumab. So it's an anti PD-1 agent in an anti-CTLA-4 TLC for antibody in combination, versus chemotherapy in patients who had a PD-L1 expression greater than or equal to 1%. This combination is already approved by the FDA for this indication, and the update confirmed that with longer follow-up there continues to be an overall survival benefit in this population.


There's also an indication that nivolumab and ipilimumab may prolong survival compared to chemotherapy in the less than 1% PD-L1 subgroup. However, this was not one of the primary endpoints of the study, and so the indication doesn't include that. But I think that that's the population that's very interesting and that we should think about addressing in further trials.


Now, the second abstract, which was new, was the CheckMate-9LA study. And that was, again, across all PD-L1 levels, advanced non-small-cell lung cancer, were randomized to nivolumab and ipilimumab in combination with just two cycles of platinum doublet chemotherapy, the idea being that for those patients with lower levels of PD-L1 that may be adding the chemotherapy may be beneficial. And we know that from other studies of chemoimmunotherapy.


So this was an intriguing design. And, in fact, it did meet its primary endpoint of improved overall survival across all PD-L1 levels of limited chemotherapy plus nivolumab ipilimumab compared to chemotherapy alone, with a hazard ratio of 0.66 in favor of the combination. And, very interestingly, the magnitude of survival benefit appeared to be the same across all PD-L1 levels, whether it was high, greater than 50%, or even less than 1%, It really was about the same hazard ratio, in the range of about 0.6 for survival.


So this is great. It certainly offers a new option for our patients. And the FDA did actually approve it, again, in May 2020 for the combination. The major question though, with both of these regimens, is they were superior to chemotherapy, and chemotherapy is no longer considered standard of care in the United States for patients with non-small-cell lung cancer. Either single agent PD-1 drugs, such as pembrolizumab for high PD-L1 or chemotherapy plus a PD-1 agent in all other levels of PD-L1 expression is already the standard of care. And so I don't know where to put this into practice, when we already have other combinations or agents in the setting. And it's not clearly, dramatically better just looking across trials.


And so I think, while this certainly offers more options for our patients, that we'll have to wait and see if there is a patient population that would benefit especially well from one of these combinations compared to what we already have available. Certainly, the toxicity is perhaps tolerable, but perhaps somewhat more than single agent PD-1 with the combination of the CTLA-4 antibody.


Another perhaps not yet practice changing but could at some point become practice changing abstract was 9503. This was a study called the CITYSCAPE study. So these were, again, first-line stage IV non-small-cell lung cancer patients. It was randomized phase II, and they were randomly assigned to either atezolizumab, the anti PD-L1 agent plus placebo or atezolizumab plus tiragolumab, which is anti-TIGIT antibody, T-I-G-I-T, which is another immune checkpoint inhibitor. And the primary endpoint was response rate and progression-free survival.


This was for everyone with a PD-L1 level of greater than 1%. And, very interestingly, there was an improvement in both overall response rate. It was almost doubled from 21% up to 37%, with the combination of the PD-L1 inhibitor and the TIGIT inhibitor, and a longer progression-free survival. But I think what we learned in the presentation that was different from the abstract is that it seems as though this it was restricted to the subgroup of people whose PD-L1 score was greater than or equal to 50%. This is already a group for which we have aztezolizumab and pembrolizumab approved, and this had a dramatically higher response rate and progression-free survival in this group, with a hazard ratio really of 0.3 compared to atezolizumab alone.


So while this is not yet practice changing, because it's just a randomized phase II and the drug is not yet approved, I do think that this is the first signal we've seen that there may be a subgroup of people with a high PD-L1 that may benefit by adding a second immunotherapy drug. And this is well worth proceeding to a phase III trial.


And then, finally, of the agents that are potentially practice changing in the relatively near future would be abstract 9504, which was the DESTINY study. This was a single agent phase II trial using trastuzumab deruxtecan, which is an antibody drug conjugate against HER2. And this was looking specifically in a cohort of patients with HER2 mutated metastatic non-small-cell lung cancer.


There were 42 patients in this cohort that were treated with the antibody drug conjugate. All of them had been pretreated with chemotherapy and/or immune checkpoint inhibitors. And very promisingly, we saw a 62% response rate with this agent, which was really probably the highest response rate we've seen of any drug in this population of HER2 mutant lung cancer.


We know that HER2 mutant lung cancer is an identifiable population of adenocarcinoma patients. It's about 2% of adenocarcinoma patients. But for the first time, we finally saw efficacy in this population with a targeted drug. Because tyrosine kinase inhibitors have been disappointing in the past. So this drug showed a 62% response rate and, very promisingly, and estimated progression-free survival of 14 months. Very comparable to what we might see with, say, an EGFR tyrosine kinase inhibitor in mutant lung cancer.


So I think this is very promising and certainly deserves consideration for our patients with HER2 mutant lung cancer. Importantly, it also was fairly well tolerated. Now, there were some patients who got interstitial lung disease from the treatment, but all of them were grade 2 and responded to steroids. And so I think that this would be not a deal breaker in terms of toxicity. And hopefully we're soon going to have to add HER2 to our list of targeted agents that will have to be testing for in non-small-cell lung cancer.


ASCO Daily News: Well, we also heard some promising news about a randomized trial for patients with oligometastatic lung cancer that could potentially affect standard of care. Can you tell us about this study?


Dr. Nathan Pennell: Yes. I think you're referring to the SINDAS study, which is abstract number 9508. So this is basically building on what we know about patients with so-called osimertinib disease. Which means that really only a few sites of distant metastatic disease. We know from trials in non-small-cell lung cancer -- and so far, just to point out, these trials are all small phase II trials -- that by doing definitive either surgery or radiation to limited sites of metastatic disease in addition to systemic therapy, that patients may actually have longer control of their cancer and may even live longer. And this is being hopefully replicated in a phase III trial.


Now, the particular trial, the SINDAS study, was looking at the EGFR mutation positive subgroup of lung cancer patients. So this is about 15% of adenocarcinoma patients. These are treated preferentially with tyrosine kinase inhibitors, which have been shown to be more effective than chemotherapy. And in this study, 133 patients who had five or fewer distant sites of metastatic disease were randomly assigned to either a tyrosine kinase inhibitor, using the first generation inhibitor, such as gefitinib or erlotinib, or the same tyrosine kinase inhibitor plus stereotactic radiation -- so ablative treatment to all of the sites of disease plus the primary tumor. The primary endpoint was progression-free survival, and the secondary endpoint was overall survival.


And while it is not surprising that this prolonged progression-free survival, because that's what we've seen consistently with this model, interestingly, there was a significant improvement in overall survival as well, with the hazard ratio of 0.68 with the addition of radiation. They did give us some breakdown of the different characteristics of the patients, and it did seem as though the number of metastases mattered. And so this might be something that could be considered more in patients who have less than two sites of disease. So really, as we know from oligometastatic disease, patients who have a single site of metastasis seemed to do better with ablative therapy, and that seems to be replicated here.


So is this practice changing now? Well, it certainly is consistent with the other phase II trials of a ablative radiation plus systemic therapy improving survival. I would like to see this replicated in a larger study before I would do this routinely. However, especially in someone who would, say, have a single site of metastatic disease, I think it would be very reasonable to consider doing radiation to that site now, based upon this data, while we're waiting for more evidence to emerge. I'm not sure I would run out and start radiating those with, say, five sites of metastatic disease, because I'm not sure that really necessarily meets the oligometastatic definition in my mind.


ASCO Daily News: And, finally, you are part of the COVID-19 and Cancer Consortium, which shared its first report at the Special Clinical Science Symposium on COVID-19 and Cancer. Briefly, how does the report shed light on the potential outcome of patients with cancer who also have COVID-19?


Dr. Nathan Pennell: Now, this, I think, was very exciting, mostly because it illustrates just how well we all come together in an emergency situation. So this was a grassroots consortium, the COVID-19 and Cancer Consortium, that was first started by some investigators at Vanderbilt University, but it came together with colleagues on social media. And before they knew it, they had gathered investigators from 100 different international sites to try to enter information on characteristics of their cancer patients who'd been infected with COVID. Because we were seeing results coming out of China suggesting that cancer patients maybe were at higher risk of both getting COVID and also having poor outcomes, and we really wanted to know how we could best serve our own cancer patients in the United States.


So in a tremendously short period of time, this consortium came together. And then they presented the results on Saturday of more than 900 cancer patients who had also been infected with COVID. Very interestingly, and concerningly, there was a 13% overall rate of mortality among patients in the cohort, suggesting that patients of cancer certainly are potentially at higher risk of dying than patients without cancers in overall infection rates. However, we had enough numbers to be able to pick out which patients may be at higher risk and not just all patients who'd had a history of cancer.


Those who had a history of cancer but that was in remission and did not appear to be current did not seem to be at any increased risk of bad outcomes, which was very reassuring. While patients who were older, who had significant conditions-- so COPD, heart disease, et cetera-- and especially those whose cancer was active and getting worse, seemed to do significantly worse and have a higher rate of dying from COVID. And so this really helps inform, for us, which patients we need to be most cautious of and would have the highest risk if they were to become infected with COVID-19.


ASCO Daily News: Well, thank you, Dr. Pennell, for sharing the highlights of that report. And we'll continue to follow the important work of the COVID-19 and Cancer Consortium. Thank you very much, Dr. Pennell, for sharing your insights with us today on the ASCO Daily News podcast.


Dr. Nathan Pennell: Thank you, Geraldine. And I really appreciate the opportunity to discuss this.


ASCO Daily News: And thank you to our listeners for joining us today. If you're enjoying the content on the podcast, please rate and review us on Apple podcasts.

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

COI Disclosure: Dr. Nathan Pennell

Consulting/Advisory Role: Astra Zeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Inivata, Genentech, Amgen, G1 Therapeutics

Research Funding: Genentech, Celgene, AstraZeneca, Pfizer, Merck, Loxo, Altor, BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jouncer Therapeutics, Mirate Therapeutics, Heat Biologics