Oncology Data Advisor: Hi, everyone. Thank you so much for joining us. Today we're here in honor of World Cancer Day with our Editor in Chief, Dr. Thomas Abrams, who is an Assistant Professor of Medicine at Harvard Medical School, as well as two of our editorial board members, Dr. Ulka Vaishampayan, a Professor of Medicine at the University of Michigan Rogel Cancer Center, and Beth Sandy, an outpatient thoracic oncology nurse practitioner at the University of Pennsylvania Abramson Cancer Center. Today they're going to be giving us an update on the latest research in the field in honor of World Cancer Day.

Thomas Abrams, MD: Thank you for having me, Keira. This is really wonderful to be representing Oncology Data Advisor on World Cancer Day. As you alluded to, I'm a gastrointestinal (GI) medical oncologist. My specialty within that is hepatobiliary cancers, but I treat all manner of GI cancers. We recently had our big meeting, American Society of Clinical Oncology (ASCO) GI, a couple weeks ago. There were actually some really major practice-changing studies presented in hepatobiliary cancer. These are cancers where, traditionally, patients don't do very well. They're diagnosed late. Patients die usually within a year of diagnosis, unless they're diagnosed very early. Having these new treatment options are really, really terrific for patients.

In cholangiocarcinoma and gallbladder cancer, there was a study called TOPAZ-1, which pitted the previous standard of care, gemcitabine and cisplatin for newly diagnosed advanced cancer patients, versus that combination with durvalumab, which is an immune checkpoint inhibitor. In case most people don't really know, immune checkpoint inhibitors haven't really become very valuable in most GI cancers. We haven't really figured out ways to use them in most colon cancers or most pancreatic cancers. Despite the value in other cancers, there really hasn't been as much immune therapy in GI cancer. This was a really important study, and it found that the addition of durvalumab to that chemotherapy backbone improved outcomes, improved overall survival, and improved response rates and progression-free survival. This was a big win for immune checkpoint inhibitors in hepatobiliary cancers.

We had another study that looked at early-stage cholangiocarcinomas that were removed surgically. Previously, there was a study looking at a drug called capecitabine adjuvantly, which didn't meet its primary end point, but there was a thought that it may improve outcomes. There is now a study in Asia looking at a drug called S-1, which is a fluoropyrimidine, and that clearly was a big win and another big improvement in treatment for resected biliary cancers.

In hepatocellular carcinoma, we also found a new immune checkpoint inhibitor study looking at two immune checkpoint inhibitors together, durvalumab and tremelimumab, which is a CTLA-4 inhibitor. One dose of tremelimumab with durvalumab showed at least as good treatment as any treatment that we've had so far. This is just purely immune checkpoint inhibitors in hepatocellular carcinoma, no other drugs involved—no TKIs, no VEGF inhibitors. That showed a very significant improvement in overall survival. So really there are three major studies that are potentially practice-changing that were presented just two weeks ago. I think we're really moving in the right direction in these kinds of cancers that have generally very poor prognoses.

Oncology Data Advisor: Thank you so much for that really great overview. So Dr. Vaishampayan, what has some of the latest research included in the field of genitourinary cancer?

Ulka Vaishampayan, MD: Yes, thank you for inviting me. I know on World Cancer Day, we're trying to sort of summarize what has happened in the field overall, as well as in specific cancers. One principle I will state right off the bat is that our cancer therapies are getting much more targeted. We are able to select our patients better and better to benefit from specific therapies, which of course improves the efficiency of treatments overall. The other thing is they are getting much more widely applicable. For instance, bladder cancer was a disease of the elderly. You could barely ever give them cisplatin-based chemotherapy, given their kidney function and all of their other comorbid conditions. But now, with other treatments like immunotherapy and antibody-drug conjugates, I think systemic therapy has become accessible and applicable to a much wider population. I would say that's true in prostate cancer and true in kidney cancer also.

Starting with kidney cancer, I think the big paradigm shift has been to use immune therapy–based combinations up front. There were reported five-year results with a sizable proportion, about 20% to 30% of patients, actually having long-term remissions starting off with metastatic disease. The other big area of controversy right now is whether to do nephrectomy in metastatic disease. Because patients who present with the kidney mass and metastases at the same time do much worse than the patients who had presented early on with just a kidney mass, they had the kidney removed and then relapsed to develop systemic disease. Right now, there is a national trial S1931 or the PROBE trial, that is addressing that question of whether removing the kidney still holds a role in the setting of such effective immunotherapy combinations for metastatic kidney cancer or for synchronous metastatic kidney cancer.

In bladder cancer, as I said, more and more, a lot of the immunotherapy mechanisms are moving earlier and earlier even in the non-muscle invasive phase, which allows us to sort of delay the appearance of metastases. This is the ultimate goal in the first place. In prostate cancer, there are already a number of therapeutic options for metastatic disease, but it does remain an incurable and morbid condition. There was a recent report of the prostate-specific membrane antigen (PSMA) lutetium, which showed efficacy and survival benefit in metastatic castrate-resistant prostate cancer. It's important to keep in mind, this modality has not yet received FDA approval, but that could be a potential therapeutic option for people in the future.

The other trend has been more and more that a lot of our effective treatments, like the oral hormonal agents and chemotherapy with docetaxel, are moving into the earlier setting. In the hormone-sensitive stage in metastatic disease, now you can use those modalities and get better survival outcomes by treating people earlier or by intensifying therapy upfront. So think about that as you are looking at the long-term for your metastatic prostate cancer patient. Of course, you have to factor in their life expectancy, their comorbid conditions, et cetera, when you're considering intensification of therapy.

Immunotherapy is gradually making a comeback in metastatic prostate cancer in very, very select patient populations. The University of Michigan has reported a CDK12 mutation that may make prostate cancer very sensitive to immunotherapy, so there are clinical trials ongoing in that field.

Overview-wise, there are a lot of exciting advances going on. There is more and more genomic profiling and testing, and even the trend towards getting liquid biopsies and being able to select our therapies. I think that is where the future is, and it does look particularly bright, although it can't be here soon enough. I will end on a note that all these advances that we've made have been because of the kindness and generosity of patients who have participated in clinical trials that help move the field forward. So tremendous thanks to all of those patients and their family members, of course, who have made the sacrifice. Hopefully, that will keep on going to move the field. Thank you.

Oncology Data Advisor: Great. Thank you so much for explaining all these advances. So to speak about lung cancer, Beth, what have some of the latest advances in lung cancer included, as well as some of the future directions?

Beth Sandy, MSN, CRNP: Thank you for inviting me. My name is Beth Sandy, I'm a nurse practitioner in the Cancer Center at the University of Pennsylvania. I've been a nurse practitioner there for 20 years treating lung cancers. I've seen a lot that's happened, and I've got to tell you, this is a really, really exciting time to be in lung cancer. I'm going to talk about a few different things: chemotherapy, immunotherapy, and targeted therapy, but I'm going to start off by just talking about some statistics.

I can tell you that this is the very first year, 2022, that the lung cancer deaths have dropped just below the deaths from colon, breast, and prostate cancer combined. Every year that I speak about lung cancer, it's always, "Lung cancer is the number one cancer killer," which is correct. It still is by far the number one cancer killer in the United States, and it was always more than breast, colon, and prostate cancer combined, which are the top three. However, this is the very first year that that number slipped just underneath of them, and that's exciting for us. Really, that is largely because of targeted therapies and immunotherapies that are helping patients with lung cancer live longer. When I first started this 20 years ago, the average survival with treatment was nine months for metastatic lung cancer. Now, we're quoting numbers around two years plus because of targeted therapy and immunotherapies, and that's just from a statistical standpoint. It's really exciting to see our patients living longer, even to five years sometimes, which was really unheard of in the beginning when I started doing this.

I'll start with chemotherapy because chemotherapy is a little bit old hat now in lung cancer. Obviously, platinum-based chemotherapy is the backbone treatment for both small cell and non–small cell lung cancer; it's still that way, though immunotherapy is now in the first-line setting. I'll talk about that in a second. A lot of times, we're combining immunotherapy with either carboplatin or cisplatin in the first-line, and a third drug, depending on the histologic subtypes. That hasn't really changed over the past three to five years. We're still doing that in the first-line setting.

The one chemotherapy drug that is new, that I'll call out attention to, is lurbinectedin. Lurbinectedin is a drug that was recently, over the past two years, approved for small cell lung cancer. Remember, in lung cancer, we have non–small cell, which makes up about 85% of the cases; small cell's around 15%, but it's very, very aggressive. We haven't done well with treating that in the past. We are using chemo and immunotherapy, but there's a new chemotherapy, lurbinectedin, that's approved in the second-line setting now, where we've had very few approvals, so that's exciting. It has pretty good response rates and is fairly well tolerated. I think that's really the only new thing in chemotherapy I would talk about.

So let's talk about immunotherapy. You have to think that probably the biggest space that immunotherapy has had its breakthrough in is lung cancer. It's been very exciting. Maybe melanoma would fight me on that; I don't know. But in lung cancer, we are now using checkpoint inhibitors in the frontline setting really for everyone, unless there is a contraindication such as organ transplant or severe autoimmune disease. Outside of that, really everyone's getting a checkpoint inhibitor regardless of programmed death ligand 1 (PD-L1) expression. Now we do test for PD-L1 expression, and if they're higher than 50%, you can actually salvage chemotherapy, wait until the second-line setting, and use just single-agent checkpoint inhibitor therapy in the front line, which really is just as good if not better than platinum-based chemo and certainly is better tolerated. It's really exciting when we can do that.

Some of the drugs even have approval for 1% or higher, though I think most of us in the field are still going to add chemotherapy if you're under 50% because you don't get as robust of a response rate. It just depends. It's not wrong even in the 50% expression of PD-L1 or higher to use chemotherapy. It's not wrong; it's just often not necessary. It depends, really, on the patient, what their feelings are, and if you're willing to just use that single agent. But it's really been a breakthrough; it's wonderful. Then immunotherapy's also in the first-line setting now for small cell lung cancer. That really hasn't changed; that's been about two or three years, as well. Really, using immunotherapy in this setting has changed our practice in the past three to five years—using it as a single agent, reducing toxicity in the frontline setting, salvaging chemotherapy to later if we can, or combining all three in the first-line setting.

Using these drugs, typically we can see median progression-free survivals of a year or more. I have a patient I saw this week in clinic who's on their five-year anniversary of single-agent first-line checkpoint inhibitor. She had metastatic disease, including brain metastases, at diagnosis and has been on a single-agent immune therapy checkpoint inhibitor for five years. She's never seen chemotherapy in her life yet. These are not super uncommon. They're not the norm, but they're not rare, I wouldn't say. So it's really exciting.

Then I'll finish with targeted therapies. Targeted therapies are going to be when we have non–small cell lung cancer. This is particular to non–small cell and even more particular to most patients with adenocarcinoma, who makes up the majority of non–small cell. We do a tissue biopsy and we would run molecular testing on that, a next-generation sequencing panel generally; you could also use the liquid biopsy that Dr. Vaishampayan had talked about. Sending off a liquid biopsy also detects these mutations and there are nine now. There's EGFR, KRAS, ALK, ROS1, BRAF, MET, RET, NTRK, and PD-L1's the ninth. There is an approved therapy for all of those I just mentioned, which is really exciting. Some of them are second-line—KRAS will be after failure of chemotherapy, and BRAF sometimes can be first- or second-line. But the rest of them generally will be used as first-line targeted therapies, which have been shown to have better response rates. Some, like EGFR, even have better overall survival by using just the targeted therapy first-line.

It's really important that we're making sure that we are testing patients for these mutations and expression levels, and that we are targeting our therapy if they have one of these. I'll just end by saying that this is even moving in into the early-stage setting—EGFR inhibitors are now approved postoperatively for EGFR mutation–positive non–small cell lung cancer. That's new in the past year. Hopefully, improving our cure rates would be exciting. Immunotherapy has now moved into the early-stage postoperative setting, as well, for stage II and III non–small cell lung cancer with a positive PD-L1 score of anything over 1%. We can give a year of immunotherapy post-surgery, post–four cycles of platinum-based chemotherapy, and then after that. There's lots changing in targeted immunotherapy, even chemotherapy, but certainly improving survival. It's a really exciting time for our patients with lung cancer.

Dr. Abrams: I think these were terrific summaries of some of the advances and the themes as we are learning more about targets. We've made more advances in some than in others, but I think the point is that we are figuring out the molecular basis for cancer. Slowly but surely, more treatments are becoming available that are targeted to specific genomic abnormalities that are driving the cancers. It's not simple. We know that it's not just genomics; there's metabolomics and immunogenics. There's a lot of different kinds of inputs that dictate how cancers respond to treatments; but as the basic science continues, the dominoes will continue to fall, and outcomes will continue to get better.

We're obviously looking for cures. Cures are hard to come by in advanced cancers, but we see them from time to time. That gives us hope that we can improve these outcomes and actually get patients to have disease freedom for years and years, which is tantamount to cure. That's the hope, and I think it's becoming more of a reality. It feels closer than it ever has. I open the floor to my colleagues to share their thoughts on that.

Ms. Sandy: We're full of exciting clinical trials at Penn looking at new targets. There are targets I've never heard of—I have to have the study nurse explain it to me—multiple different immune checkpoints that I've never heard of, and we're just combining these drugs together. Sometimes the toxicity's bad, but we learn to deal with it or manage it in some way. That's our future really in lung cancer: combining new checkpoint inhibitors for the immune system and combining those with either old checkpoints or other drugs. Then on the other side of it is learning about new targets. We're up to nine; can we find more? Maybe HER2's around the corner for us in lung cancer like it is in breast cancer. We're really looking at that, and I think that's going to be something coming up, too.

A lot of people will say, "Well, HER2 mutations and RET and MET only make up 1% to 2%." But if you start adding up all that 1% to 2%, that ends up being 5% to 10%. Then you say, "Well, that's a large chunk of patients"—I think it's around 300,000 of these a year. That becomes a large number to really impact those lives. Research is really strong in that area of looking at immune therapy and targeted therapy, for lung anyway.

Dr. Abrams: I think you bring up a really good point, which is that at some level, we're going to have to start deviating from sort of organ-specific disease thinking, because a HER2-amplified lung cancer is clearly not the same thing as a non-HER2. Maybe it's more akin to other HER2-amplified cancers in general. I think we're going to be getting away from this sort of organ focus and move into genome focused. Maybe that's going to be a new paradigm, but this is obviously longer term. I do see that as a thing that we should be thinking about, at least; because clearly, within colon cancer and within pancreatic cancer, you see great responders who do it tremendously well, and then you see really poor responders who have horrible outcomes. We don't really know why that is, but obviously, there's a reason for it. By searching and trying to continue the research, I think we will find that there are parallels between diseases we didn't really think there were. I think the approach is going to change.

Dr. Vaishampayan: I completely agree with the comments before. I also think that the more we use this kind of personalized therapy, we are getting more rapid access to our patients for the new drugs. Now you can do just a single-center, small, 50-patient study which shows proven benefit because you're selecting the patients so carefully as those who are most likely to benefit. Compared with the hundreds and thousands of patients we put on clinical trials before, they showed a difference from 20% to 40%, for instance, was not as big an advance. I would say that clinical trials, for my patients, represent the most cutting-edge science there is.

I would advise most of the patients to at least consider that when they're considering therapy choices and not wait until they fail everything else to consider clinical trials. That is not the role of clinical trials anymore; it has changed so that it's ongoing throughout the disease process. The three R's that I claim for our phase 1 team are rapid access to the right agent to the right patient. That's really the goal going forward: to develop more and more ways and technology to get there in terms of personalized medicine.

Oncology Data Advisor: Thank you all so much for sharing this research, and it'll be really exciting to see how the field continues to evolve in the future.

Dr. Vaishampayan: Absolutely. Thank you.

Oncology Data Advisor: Thank you to everybody for tuning in today.

Thank you for listening to Oncology Data Advisor. Be sure to subscribe to the podcast so you'll never miss an episode. In addition to our podcast, the Oncology Data Advisor site features expert perspectives and news stories on the latest in cancer research and treatment, all found at OncData.com.

About Dr. Abrams, Dr. Vaishampayan, and Ms. Sandy

Thomas Abrams, MD, is an Assistant Professor of Medicine at Harvard Medical School, a Senior Physician at Dana-Farber Cancer Institute, and the Director of the Liver Cancer Task Force of the Harvard Cancer Center. He specializes in the treatment of patients with gastrointestinal cancers, including pancreatic, gastric, colorectal, esophageal, gallbladder, and primary liver cancers. Dr. Abrams' primary research interest is the early detection of liver cancers through the discovery and application of novel biomarkers. He has authored or coauthored numerous publications in peer-reviewed journals.

Ulka Vaishampayan, MD, is a Professor of Internal Medicine and the Director of the Phase 1 Program at the University of Michigan Rogel Cancer Center. She is also the Chair of the SWOG Advanced Renal Committee, a member of the National Cancer Institute (NCI) Renal Task Force, and a board member of the Michigan Society of Hematology/Oncology. Dr. Vaishampayan specializes in the treatment of genitourinary malignancies, including prostate cancer, bladder cancer, and renal cell carcinoma, and her research focuses on translational drug development. She has authored or coauthored numerous publications in peer-reviewed journals.

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 or 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.

References

Oh DY, He AR, Qin S, et al (2022). A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1 [oral presentation]. Presented at: 2022 American Society of Clinical Oncology Gastrointestinal Symposium. Abstract 378. DOI:10.1200/JCO.2022.40.4_suppl.378

Ikeda M, Nakachi K, Konishi M, et al (2022). Adjuvant S-1 versus observation in curatively resected biliary tract cancer: A phase III trial (JCOG1202: ASCOT). Presented at: 2022 American Society of Clinical Oncology Gastrointestinal Symposium. Abstract 382. DOI:10.1200/JCO.2022.40.4_suppl.382

Buchalter J, Browne I, Eochagian CM, et al (2022). Tremelimumab (day 1 only) and durvalumab in combination with transarterial chemoemobilization (TACE) in patients with hepatocellular carcinoma (HCC). Presented at: 2022 American Society of Clinical Oncology Gastrointestinal Symposium. Abstract 481. DOI:10.1200/JCO.2022.40.4_suppl.451

Clinicaltrials.gov (2021). Comparing the outcome of immunotherapy-based drug combination therapy with or without surgery to remove the kidney in metastatic kidney cancer, the PROBE trial (PROBE). NLM identifier: NCT04510597.

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