Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're here doing a live interview in honor of World Lung Cancer Day. I'm joined by Beth Sandy, who's one of our editorial board members, as well as Dr. Corey Langer. Thank you both for joining us. Would you like to introduce yourselves?

Beth Sandy, MSN, CRNP: I'm Beth Sandy. I'm a Nurse Practitioner in the Cancer Center at the University of Pennsylvania in Philadelphia, and my primary practice specialty is lung cancer. With me, I have the Chief of our Thoracic Oncology Department. Dr. Langer, do you want to introduce yourself?

Corey Langer, MD: Sure. I'm Corey Langer. I am the Director of Thoracic Oncology, what we call the ITOP, the Interdisciplinary Thoracic Oncology Program, at the University of Pennsylvania Perelman School of Medicine. I'll reintroduce Beth as really one of the first, if not the first, Thoracic Oncology Nurse Practitioners not just at Penn, but I think in the Delaware Valley. You're the prototype, Beth. 

Ms. Sandy: Getting old.

Dr. Langer: Not that old.

Oncology Data Advisor: We're excited to hear today about some of the latest advances in immunotherapy and targeted therapy. With that, Beth, I'll let you take it away.

Ms. Sandy: Thank you, Dr. Langer, for joining me. We just wanted to really give a positive update on all the things going on with lung cancer now. Why don't we start off with immunotherapy? Let's go there first—where we've been, where we are now, and any American Society of Clinical Oncology (ASCO) updates that you think are interesting from this year. Take it away.

Dr. Langer: Immunotherapy, particularly for those patients with the metastatic recurrent disease and those who do not have oncogenic drivers, has really led to a revolution in how we practice. It's irrevocably altered the therapeutic landscape. We generally approach these patients based on their programmed death ligand 1 (PD-L1) status. For a PD-L1 of 50% or higher, we use pembrolizumab (pembro) alone or pembro plus chemo, really depending on the clinical situation. There are a number of trials now, of course, looking at new combinations. For those with less than 50%, at least it's our practice to give histology-specific chemo plus pembro.

All these approaches have led to monumental improvements in survival. When you and I started out, Beth, median survival at best was 10 to 12 months. One-year survival rates, if we hit 40%, we were grateful. If we hit 20% two-year survival, that was astounding. When I started out actually, the median survival was about six months. We made major headway with regimens like the KEYNOTE-189 approach. Median survival for non-squamous non–small cell without oncogenic drivers is about 22 to 23 months. Even our progression-free survivals (PFS) are exceeding what used to be our survival rate, so it's really quite astonishing.

We've seen some recent updates in five-year survival. For instance, in the KEYNOTE-024 trial, if we look specifically at the patients who are receiving single-agent pembro for 50% or higher PD-L1 expression, their five-year survival rates are approaching 30% to 33%. About a third can expect to be alive.

Ms. Sandy: I know, I found that to be amazing—a third of patients are surviving five years with metastatic disease in that high P-DL1 subgroup.

Dr. Langer: This is without chemotherapy. This is without a platinum combination.

Ms. Sandy: I know, it's amazing. I even saw something recently that Dr. Marmarelis, one of our people in our group, had put out that even the 90% and higher do better. It's worth checking to see if they're more than 90%.

Dr. Langer: I think there's a tendency to divide everybody into just three basic groups—less than 1%, 1% to 49%, and 50% are higher—but there are definitely nuances. If we look at the really high expressors, 80%, 90%, 100%—I guess there's no such thing as 100%, but 95%—we are seeing relatively better median and long-term survival. It's definitely a continuum, particularly above 50%. Intriguingly, there are some studies now that are essentially segregating out or basing their results on 50% to 74% and 75% or higher.

Ms. Sandy: Differing the cut point.

Dr. Langer: Yes.

Ms. Sandy: Tell me what you think about moving now immunotherapy into the early-stage setting, with data now for looking at drugs like atezolizumab in the adjuvant setting and nivolumab in the neoadjuvant setting. What are your thoughts there?

Dr. Langer: Here too, just in the last two years, we've seen major advances. Obviously, the metastatic recurrence setting is really the proving ground for new agents, but if it's going to make a real difference in overall survival and cure rates, it's got to be moved to the resectable or locally advanced setting. I think all of that started of course, with PACIFIC and the addition of durvalumab (durva) for up to a year post–definitive chemoradiation. There, we're seeing a 43% five-year survival. Remember that historically, at best, it was about 15% to 25%. That in and of itself is quite amazing, and now it's been moved even earlier in the adjuvant or neoadjuvant setting.

The IMpower010 trial looked atezolizumab in patients who had undergone definitive resection and adjuvant platinum-based chemo for four cycles after resection of stage IB through IIIA disease. There was a clear-cut disease-free survival (DFS) benefit for those with node-positive PD-L1–positive tumors. When you slice and dice the data, though, it gets a little bit more nuanced. The greatest benefit was in 50% or higher. It's a little less evident for the 1% to 49%, and there's no approval below 1%. I think I embrace that approach with enthusiasm, certainly for those with higher expression, with some degree of ambivalence for the 1% to 49%. Remember, we do not yet have overall survival (OS) data. I think once we get the overall survival data, we'll be a bit more compelled or a bit more convinced.

The neoadjuvant setting is an area that we haven't typically explored all that much at Penn, certainly not with just chemo alone, although pre-dating my arrival, that was used a lot. The addition of nivolumab to histology-specific chemo, in some cases just paclitaxel/carboplatin (pac/carbo), has led to a major improvement in pathologic complete responses and major pathologic regressions, which are defined at 90% or greater shrinkage and no harm when it comes to surgery. In fact, the resection rates, if anything, are a bit higher than the control group, and pneumonectomy is slightly less common in the group that got neoadjuvant. That too is now translated into a DFS benefit, that 11-month improvement.

The big struggle there is, which patients are we going to use that approach on? Two-thirds of the patients accrued had IIIA disease, and I think that's where we're concentrating our artillery. This is a group where the surgeons probably don't necessarily want to operate upfront.

Ms. Sandy: I mean, that's the majority of where we give neoadjuvant treatment anyway, those IIIA, right?

Dr. Langer: Historically, we were approaching those folks with chemo or, more commonly, chemo/radiation, then trying to do surgery. The notion that we can substitute immunotherapy for radiation and get hopefully as good or better outcomes, is really quite novel.

For stage IB or II, the surgeons can operate on those folks upfront, and if they're eligible, they will then go onto atezolizumab if they qualify post-resection and post–adjuvant chemo. We really have an array of options, and to be blunt, none of this was even on our radar 10 or 12 years ago. The immunotherapy approvals only emerged in 2015 and 2016, and the first-line approvals in 2018, only four years ago.

Ms. Sandy: That's really cool. Let's switch gears now and talk about targeted therapy, our other area of huge improvement in lung cancer. Again, Corey, back in the early 2000s when I started doing this, we didn't know about molecular testing and biomarkers and how they're driving cancer, and now we have nine that we can target.

Dr. Langer: Nine and counting.

Ms. Sandy: I know, you're right. It's just amazing. I mean, I don't even know where to start with all nine. Obviously, we can start with the early ones we knew about, the EGFR, ALK, ROS1, and that's just really snowballed now into RET, MET, KRAS. From my standpoint, before I let you talk about it, we have to do the testing. We are getting better. There was a great article last month in the Journal of Thoracic Oncology, looking at how we are improving testing, especially in community. It looked at academic and community testing, but it still shows about a third of eligible patients, those non-squamous, particularly adenocarcinoma patients with non–small cell lung cancer, still not getting a full broad molecular panel. We have to do the testing in order to find these. And you will find them, not in everyone, but we will find these targets if you're testing. What are your thoughts on testing and these targeted therapies?

Dr. Langer: I think your point is very well made. If you don't look, you won't find. Very early work from the Lung Cancer Mutation Consortium showed that folks who had oncogenic drivers and received the appropriate targeted therapy did far better than those who did not have oncogenic drivers, the tumors that weren't harboring these molecular aberrations, or those who harbored the molecular aberrations but did not get appropriate molecular therapy. Early on, the survival advantage was evident.

The big issue, of course, is the turnaround time and getting the test results. Next-generation sequencing (NGS), at best, can be done within maybe two weeks of biopsy. I think on average, at our institution and elsewhere, it's three to four weeks. It's labor intensive, it requires batching and staining, it's a big panel. It gets doubly difficult if we're trying to procure specimens from outside as opposed to those obtained in-house. Then sometimes, even after the most diligent work, the DNA is degraded or denatured. You get that awful result, quantity not sufficient (QNS), so all that work is ultimately for nothing.

We have been on the forefront of initiatives looking at paired tissue and liquid biopsies. We actually have an initiative at Penn, where as soon as a patient with metastatic recurrent disease—certainly non-squamous, but even squamous to some extent—gets registered in our system, we are making arrangements for a liquid biopsy. The liquid biopsies are getting better and better. They're steadily improving in sensitivity. They're still not as good as tissue sensitivity, maybe 70%. If the tumor burden is low, maybe just confined to the chest, the likelihood of discovering or identifying molecular aberrations in the blood goes down. The specificity is very good. It's close to 98%/99%. If you discover it in the blood, it's real and you will almost definitely find it in the tissue.

These two approaches complement each other. When we first piloted this approach, our identification rate with tissue alone was maybe 20%/22%. When we added liquid, it went up to 35%, so 15% absolute improvement in the number of patients we identified who could be treated with an appropriate oncogenic driver.

Charu Aggarwal, who's the Head of Personalized Medicine Initiatives at Penn and really one of the stellar players in our thoracic oncology group—she also leads the Asthma and Airway Disease Research Center Clinical Research Unit within our institution—she and Dr. Jeff Thompson from Interventional Pulmonary and Erica Carpenter, a non-MD molecular biologist who's in charge of the Circulating Tumor Lab, have started other initiatives looking at guideline-concordant testing. Doing the two types of testing together improves our guideline concordance by up to 90% to 95%.

Folks who get tested early—those who we are able to identify, get their oncogenic results, and delay treatment until we get those results, basing our treatments on the full panel—they have better outcomes. Their survival rates are better than those we initiate with the incomplete results. That's in large part because A) we're identifying more oncogenic drivers, and B) we're avoiding the inappropriate use of immunotherapy in a group that would preferentially benefit from targeted therapy.

It's really been a landmark approach. Charu had the privilege of presenting her data during a poster discussion at ASCO, and I think it's one of the more important papers. It was a series of more than 300 patients from our institution, over a two-year period, ending in 2020. There too, we have osimertinib clearly superior to older first-generation tyrosine kinase inhibitor (TKIs) like erlotinib and gefitinib, not just in progression-free survival, but in CNS penetrance. Sadly, the final common pathway for many of these patients is CNS disease, increasingly leptomeningeal disease. I don't know about you, Beth, but I think in the last two years, I've seen more leptomeningeal disease than I saw in the previous 20 years.

Ms. Sandy: Well, I think we're controlling the body disease better and it's just giving them time to develop the CNS.

Dr. Langer: Unfortunately, it's a devastating event when it occurs. Our therapeutic armamentarium there is limited, so it's really the new frontier, a major unmet need.

We've seen major advances in ALK. At one point, I thought we had more ALK agents than we had patients, but those numbers are clear. About 4% to 8% of those with non-squamous non­–small cell have ALK, and EGFR, depending on which region in the country, could be as high as 20% to 25%. In our area, it's about 15% to 17%. We've got three great agents for ALK: alectinib, brigatinib, and lorlatinib, all better than their predecessor, crizotinib. For RET fusion, only in the last two have we seen approval of selpercatinib and pralsetinib, with response rates of 60% to 70%. They have a PFS of 18 to 20 months, really in the range of the EGFR data.

Ms. Sandy: They've got really good, durable responses in those patients. I definitely get hypertension in some of those RET patients though, so it's something to certainly look out for.

Dr. Langer: To some extent, there are a lot of off-target effects that we have to be cognizant of. Frankly, in many ways, this is more of a challenge than chemo. Chemo's very predictable; you get the fatigue, and there may be some nausea, you get mild suppression, but it eases up after 10 to 14 days, and you can predict what's going to happen. The side effects here can be delayed, they can be severe, they can be mild without making many changes, they can go from severe to mild; really, the art of medicine is managing. Frankly, Beth, you're on the forefront of that management. The initial calls go into to you folks.

Ms. Sandy: Yeah. Tell me a little about KRAS. I'd like to hear about that before we end.

Dr. Langer: KRAS is quite intriguing. It really is the most common oncogenic driver, but until the last two years, it was totally un-targetable, in part because of the shape of the structure of the receptor. It was very hard to target. We've seen the development now of two drugs and counting, one of which is now approved, sotorasib. Another one will be imminently approvable, adagrasib. Both, in the second-line setting, have response rates about 35% to 40%—not quite as stellar as we've seen with the ALK, RET, ROS1, and EGFR inhibitors, but still quite respectable, certainly something we'd choose ahead of docetaxel, I would say.

Ms. Sandy: Those patients will respond a lot of times to chemoimmunotherapy pretty well upfront, whereas we don't see that as much with the others, like EGFR, ALK, and ROS1. These KRAS patients, often they get good responses to chemoimmunotherapy upfront, so we're generally using these drugs, specifically for the KRAS G12C. But it's in that second-line setting, so it's a little bit different than what we're used to with those other drivers, where we always use it up front. We're now using these drugs second-line.

Dr. Langer: The PFS is only about 6.5 to 7 months, so it's not quite as good. Survivals are 1 to 1.5 years, so I agree it's second-line. There are two challenges there; one is to make that better to the point that we might consider frontline. There, at least the rumors state, it's been a bit hard combining sotorasib with some of the standard checkpoint inhibitors. It's not clear if that difficulty will extend to other agents. Adagrasib may be a bit more combinable, but adagrasib also seems to have a bit more toxicity. It becomes a dealer's choice.

The other issue, of course, as you pointed out, Beth, only about half those with KRAS mutations have G12C; the others are not yet targetable. Another area of major unmet need is the remaining KRAS patients. You add all this up: KRAS, EGFR, ALK, ROS1, RET, MET, HER2, NTRK. Particularly if we include KRAS, it's probably 55% to 60% of our patients. If you subtract KRAS, then it's only about 35%, but it's still a huge number. It's really incumbent upon us to identify these oncogenic drivers as quickly and as sufficiently as we can. Otherwise, we're depriving folks of life-prolonging therapy that doesn't just prolong the life but improves quality of life by and large.

Ms. Sandy: Certainly. Anything else you want to end with, any final thoughts on the state of lung cancer today on this World Lung Cancer Day?

Dr. Langer: I think the other major initiative where we're going to see a lot more data going forward is a new class of compounds called ADCs, antibody-drug conjugates. They're unique. The antibodies identify a specific antigen or receptor on the cancer cell. Then, through a linker, they essentially deliver a cell poison, a toxic payload, a chemotherapy drug, if you will, but something that can be delivered directly to the tumor and preferentially penetrate the tumor and avoid collateral damage to normal cells.

The first example of this in the thoracic world is trastuzumab deruxtecan. It targets human epidermal growth factor receptor 2 (HER2), and remember, it's trastuzumab. We think of HER2-targeting agents as really in the breast cancer realm, but up to 3% of patients with non-squamous non–small cell lung cancer have HER2. Phenotypically, they look like EGFR and ALK patients—generally never-smokers, probably a somewhat higher proportion of women—and this targeted delivery system yields a response rate of 55%. It's a PFS of about 8 months, so it's clearly in the second-line realm. It's unclear whether it's going to move into the first-line realm. There's some toxicity; the big concern is interstitial lung disease. Although it can be steroid-responsive, it can be devastating. I think in the final reports, there were two punitive fatalities attributed to it.

Really, we're taking targeted therapy and moving it beyond oral agents into the ADC world. I think certainly for the next three to five years, we're going to see that, and we're going to see new immunotherapy combinations using some drugs many of us haven't even heard of yet. I think this will ultimately make a difference both in PD-L1 50% or higher, and then the larger group of those with less than 50% expression.

Ms. Sandy: All right, thank you so much. I'm looking forward to new immunotherapy combinations and getting new immune targets like TIGIT, LAG-3, and things like that, combining those with our current PD1 inhibitors or new PD1 inhibitors. Just looking at these different combinations, I think this is what I have to look forward to and what we are seeing in clinical trials here, which is exciting.

Well, thank you, Dr. Langer, for joining us, and Keira, I'll send it back to you.

Oncology Data Advisor: Thank you both so much. It was so exciting to hear about all these new advances and all the work that's being done, so thank you again for your time today.

Dr. Langer: Thank you, take care.

Ms. Sandy. Thank you.

About Ms. Sandy and Dr. Langer

Beth Sandy, MSN, CRNP, is an Outpatient Thoracic Oncology Nurse Practitioner at the University of Pennsylvania Abramson Cancer Center in Philadelphia, Pennsylvania. She specializes in the treatment and supportive care of patients with lung cancer and other thoracic malignancies. Ms. Sandy has authored and coauthored numerous peer-reviewed publications, posters, and book chapters, and has been a speaker at several national and international conferences. She is a member of several professional societies and is active on committees and editorial boards for APSHO, IASLC, MASCC, ONS, and SITC.

Corey Langer, MD, is the Director of Thoracic Oncology at the University of Pennsylvania Abramson Cancer Center and a Professor of Medicine at the Hospital of the University of Pennsylvania. He specializes in the treatment of patients with thoracic malignancies, and his research focuses on the role of immunotherapy in advanced non–small cell lung cancer (NSCLC), the role of targeted agents in oncogene-driven NSCLC, new therapeutic strategies for small cell lung cancer (SCLC), and outcomes in underserved populations.

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Transcript edited for clarity. Any views expressed above are the speakers' own and do not necessarily reflect those of Oncology Data Advisor.