Forging Ahead in a Time of Crisis

Gandara is the director of the thoracic oncology program and senior advisor to the director of the University of California Davis Comprehensive Cancer Center.

The coronavirus disease 2019 (COVID-19) pandemic has greatly impacted all areas of the medical world. While nurses and physicians on the front lines search for answers on how to treat this novel disease, oncologists and cancer care providers around the world search for answers of their own. Should treatments be continued or halted? Should surgeries be postponed? And how can the same standard of care in be delivered in a socially distanced world? 

ONCOLOGY^® recently sat down with David R. Gandara, MD, director of the thoracic oncology program and senior advisor to the director of the University of California (UC) Davis Comprehensive Cancer Center, to discuss the impact of the pandemic on the current management and treatment of patients with lung cancer, as well as the future of education and patient care in a post–COVID-19 world. While the crisis may have “dramatically changed how we practice,” Gandara says, “it hasn’t altered the basic premise that lung cancer is now a highly treatable disease.”

Q: COVID-19, a respiratory pandemic, is obviously the biggest news in the world right now. How has that changed the way you practice as a lung cancer physician and the way you research?

Gandara: Well, what has happened has dramatically changed how we practice, how we interact with lung cancer patients. But it hasn’t altered the basic premise that lung cancer is now a highly treatable disease, that it is both genomically and immunologically complex, and that we want to offer our patients their best therapeutic options.

That being said, right now at UC Davis and most other community and academic cancer centers around the United States-including the National Cancer Institute, which has allowed this for patients on clinical trials-we have converted all of our routine follow-up to virtual or video virtual visits. I just had my first series of those in the past 2 weeks. I can visually see the patient and they can see me. I can see their scans and their laboratory results and talk and interact with them. This is now a forum for seeing patients that is accepted by insurers, including CMS for Medicare. Although virtual visits don’t have, of course, the ability to do a physical exam on the patient, for routine care of cancer patients, even those receiving cancer chemotherapy, it’s a way to have those interval or interim visits without exposing them to the risk of coming in to our office and possible exposure to COVID-19.

At UC Davis Cancer Center, everyone entering the door has their temperature taken and [is administered] questions regarding possible symptoms that could be associated with COVID-19. If they have either an elevated temperature or symptoms, they don’t come into the cancer center and are referred instead to a COVID-19 center at UC Davis. There, we would engage them and work them up for COVID-19, depending on what the situation was.

So, this is a huge change. Of course, a lot of our cancer drugs now are oral, so the patient doesn’t have to come into the infusion center. But a lot of them, including the checkpoint immunotherapeutics, are intravenous. In that case, the patient comes into the cancer center after they’ve been checked, and they get their cancer treatment through the infusion center in a very safe manner-as safe as possible. But if they didn’t need to see the physician in a separate visit, then they don’t face-to-face. That’s done virtually. 

Q: Obviously, patients with lung cancer are a uniquely vulnerable patient population. Have you had to change treatment plans at all in light of the virus?

Gandara: We’re dealing with a population who has a cancer which either started or is still present in their lung. Many of them, if they were smokers, have chronic obstructive pulmonary disease. They are older patients in general, although, of course, as everyone knows, we do have a cohort of patients who are young, never smokers, women. But most are older and previous smokers, so they are at higher risk. There is a considerable debate, not only in lung cancer, but around the United States for all types of cancers, about whether we should alter our therapy, whether we should withhold chemotherapy or immunotherapy, or whether should we give it on schedule. 

I did a social media poll last week and asked practicing oncologists whether they would arbitrarily hold either chemotherapy or immunotherapy or neither or both in a lung cancer patient. Of 357 people who responded, almost 70% said no, they would treat patients on schedule, assuming that they don’t have active COVID-19 infection. A small percentage, about 10%, said they would hold chemotherapy, 5% said they would hold immunotherapy, and about 5% said they would hold both. But the great majority would treat patients on schedule. In this social media poll, I also had a number of patients who independently responded with their views, and every single one of them said, in effect, “I know that COVID-19 may kill me, but lung cancer untreated will kill me, so please treat us like you are treating us every week.” So, although there is considerable debate about this, and some institutions are holding therapy, my own belief, and that of our institution, is that we should treat patients if we can do it safely.

Q: It seems like this is where medicine was headed in the first place, but the COVID-19 experience has super-charged the move toward more virtual medicine and doing more things online rather than face-to-face.

Gandara: Yes, I think we were moving in this direction already, and this accelerated the pace. Obviously, we have regularly scheduled WebEx CME, grand rounds, and a variety of other [presentations] that we do, and there is good uptake by attendees. It has very often been difficult for physicians, except on an occasional basis, to take off from a practice or from their academic research to attend a meeting face-to-face. But attending virtually is easier, and also, if there is enduring material from it, then that physician could, for example, view it at night, after they have dinner and have some free time. So, yes, we’re moving more quickly in that direction.

Q: At the upcoming International Lung Cancer Congress^® (ILCC), what events and discussions are you most excited to attend?

Gandara: I think I should start with saying that our ILCC is a unique CME experience, because it’s purposely placed about 6 weeks after the annual ASCO meeting. Faculty and attendees will have heard the news and the advances that are presented there, and then at ILCC, they’ll be able to listen to expert faculty and interact with them about the new information. I’ve always referred to our meeting as a think tank, because it’s much more like that than like a regular meeting. It has not only classic lectures, but it has a number of panel discussions with experts, multidisciplinary, including all the disciplines that are involved in lung cancer or thoracic malignancy care. The new and important things this year-we’re still early in the year-or I would maybe say for 2019-2020 so far, are new drug approvals. We have quite a variety of those. We [also] have new guidelines about how to use liquid biopsy. [Plus,] we have increasing information about lung cancer screening; we believe lives have been saved because we’re finding patients with earlier-stage disease. So, a whole variety of things are new, that are educational opportunities, that will be presented at ILCC 2020.

Q: Are you especially looking forward to certain sessions?

Gandara: At ILCC each year, we have a session on new drugs that are coming out and new classes of drugs that are available. That will be a highlight of this meeting. In particular, although new findings have occurred in several drug classes, one that is brand new is the development of drugs for KRAS G12C mutation. KRAS has been an undruggable target-I’ve always said this myself-because of the difficulty in developing a drug that could inhibit that mutation. But now we [do] have drugs, and 5 of them are in development and we’ll be hearing about them at ILCC. That will clearly be a highlight.

Q: How does the virtual nature of the meeting change things?

Gandara: It’s not the same as a face-to-face meeting, obviously, but an advantage is that you can incorporate attendees who are not able to physically travel to Huntington Beach for ILCC. You’re also able to broaden the scope of the faculty, because some faculty, for instance, will be coming from Europe or Asia, and as COVID-19 evolves, they and we may still have travel restrictions. So even if there’s a face-to-face component, having a virtual component will be important. We also will be able to have enduring material, which is developed in a more comprehensive way because the entire meeting, of course, will be audio- and videotaped. So not only attendees, but sponsors as well, will be able to have this information available for educational purposes of their own.

Q: Jumping to a broader clinical question, we’ve seen so many advances in lung cancer over the past 10 years. What major trends or developments do you anticipate seeing in the near future?

Gandara: So many rapid advances have occurred in the therapeutic options for lung cancer, and also in diagnostics, that it’s hard to believe that they could continue to come at such a fast rate over the next year or two. But already we have a number of challenges and opportunities which have [evolved from] these advances. I’ll just give you 1 example: We now have 8 oncogene-driven lung cancers, non–small cell lung cancers (NSCLCs), that are recognized in guidelines. You should test a patient’s tumor for these oncogenes before offering therapy, and we soon will have number 9 because I’m sure the KRAS G12C will soon be FDA approved. With that, it’s even more important for practicing oncologists to realize that even a patient who is a previous smoker might have 1 of these 8 or 9 oncogenes. [In fact,] KRAS G12C is associated with smoking, and the best treatment for [patients with a KRAS G12C mutation] is a targeted therapy rather than chemotherapy or immunotherapy or even a combination of the 2.

Another example, related to diagnostics and molecular testing: We already know that patients with EGFR-mutated lung cancer, patients with ALK-translocated lung cancer, don’t fare well with checkpoint immunotherapy. They do much better when treated with targeted drugs. So how does a practicing oncologist then test for all of these oncogenes in a time-efficient manner, with good sensitivity, good specificity, and have a turnaround time of 1 to 2 weeks, so that they can treat the patient with a personalized or precision medicine approach rather than empiric? We now have that ability, and liquid biopsy is bringing us that faster, next-generation sequencing and tissue is bringing us that, so that it can all be done simultaneously, rather than testing for one gene right after the other, sequentially, which takes a long time, and if it’s a tissue, would use up all the tissue. That’s another example of where we have opportunities to move the field forward. 

Q: Have you noticed any sort of overarching theme or clinical development, especially one that will be reflected at ILCC?

Gandara: The theme of personalized medicine, of course, has been present for several years, and it continues to grow. I’ll give you a perspective on this. With the recognition that in advanced-stage NSCLC, checkpoint immunotherapy plus platinum-based chemotherapy is very effective, there has been some divergence of opinion about what that means. Some people say, “This makes things simpler, because I can just treat everybody who comes in the door with advanced NSCLC with this regimen.” But many other people, including myself, say, “No, this actually makes things more complex, because even with the efficacy of the combination of checkpoint immunotherapy and platinum-based chemotherapy, we need to make sure the patient who comes in doesn’t have one of the oncogenes and would [in fact] be better served by a targeted therapy.”

 So, at ILCC this year, we will continue to define that personalized medicine approach. One component of this is a special part of the meeting, a molecular tumor board, with case presentations, and the audience is asked, with audience-response devices, “What would you do in this case? Would you empirically treat the patient? Would you wait until the testing comes back?” [Another component] of the meeting is the Addario Lectureship, named after Bonnie Addario from the Addario Lung Cancer Foundation, which has a precision medicine team. Each year, a world-recognized lung cancer oncologist is chosen for that award. Last year, the awardee was Solange Peters from Switzerland, and she is the president-elect for the European Society for Medical Oncology. We have already made our selection for this year, which would be July 2020 when ILCC occurs, but of course I cannot tell you who the awardee is yet because it is secret until close to the meeting. But I will tell you that as part of this award, the awardee is featured on a big billboard at Times Square in New York City. Their picture is there for an entire day, the same day as the presentation. So, assuming we’re through COVID-19 by the end of July, all of this will happen in real time.

Q: Can you discuss some study results that have been published in the past year or so that might be considered transformative or practice-changing?

Gandara: I think one [transformation] would be in regard to RET fusions. We have had some nonspecific drugs-and when I say nonspecific, they’re multitargeted-which had activity against RET before. But now we have multiple drugs which are either just approved or have breakthrough designation for RET; these are much more targeted against the gene and much more active. One of those drugs is called LOXO 292, and the response rate in patients with these fusions is 75% or above. That sort of thing is happening in many areas of lung cancer oncology.

Another example would be in extensive-stage small cell lung cancer (SCLC), where we literally have had no major advance in more than 20 years. Platinum chemotherapy, at least in the United States, remains the standard of care. Now, that being said, in this past year we have seen 2 new regimens based on adding a checkpoint inhibitor to that same platinum–etoposide chemotherapy base, and in two phase 3 studies, that combination regimen showed superior response and progression-free survival, and also overall survival was better with the combination compared with the platinum chemotherapy alone. So now 2 drugs-2 checkpoint inhibitors, atezolizumab and durvalumab-are approved for extensive-stage SCLC.

These advances are not just in one area or the other: They’re in multiple areas. Again, what that means is that a practicing oncologist has to stay on top of the field, [which can be] increasingly difficult, and the best way to do that is by CME such as we’re providing in our meeting.

Q: Looking forward, what other studies do you anticipate coming out in the next year or so?

Gandara: One opportunity that comes up is that if a checkpoint inhibitor plus platinum chemotherapy is more effective than chemotherapy alone in extensive SCLC, [can we see what happens] if we move it to the one-third of patients who have limited-stage SCLC? Here, we know already we can cure a percentage, but it’s probably no better than 25%. Could the addition of checkpoint immunotherapy actually increase the cure rate in limited-stage disease?

Moving back to the oncogene sphere, another opportunity would be in an EGFR tyrosine kinase inhibitor (TKI)-resistant lung cancer, or even in initial therapy where we have 5 drugs-all very good drugs, TKIs-to treat EGFR-mutated lung cancer. But, invariably, even with what could be considered the best of these drugs, osimertinib (Tagrisso), acquired resistance occurs. So, a multitude of trials are ongoing, to try to see if we can enhance the activity of these already very good TKIs in the management of EGFR-mutated lung cancer. Some are combinations of TKIs, and some are combinations of a drug like osimertinib with an EGFR monoclonal antibody such as necitumumab (Portrazza). Some of these are adding chemotherapy, platinum chemotherapy, to the TKI, and others are adding antiangiogenic agents. Not all of these will be superior, and some will also be associated with more toxicity. So, we’ll have to look at the risk and benefit that come out of these trials. But these trials are clearly important to do, and we’re looking forward to the results.

Q: Let’s discuss your research a bit: You’ve been very involved with the Lung-MAP protocol, correct?

Gandara: Lung-MAP is a huge, one-of-a-kind undertaking. It is the only master protocol which has regulatory intent in all the substudies. It is also the only master protocol which is a public–private partnership among the National Cancer Institute with its cooperative groups, the Foundation of the National Institutes of Health (NIH), the Friends of Cancer Research, and now more than 15 pharmaceutical companies who have partnered to develop their drugs within this paradigm.

The other thing that’s unique about it is that we have next-generation sequencing as the foundation for determining whether oncogenes are present or not. That partnership is with Foundation Medicine. We have enrolled more than 2000 patients to date, and we have completed about 10 or 12 substudies so far. So, this is meant to be self-sustaining. We continually have new studies opening and other studies closing. It’s a new way of developing drugs for lung cancer, hopefully ruling out drugs or drug combinations that are not active and doing it very promptly. On the other hand, we are able to screen large numbers of patients- we’re screening 1500 patients per year with lung cancer-so we can test drugs even in rare genotypes. That means [a lot] if, say, a gene [is present in] only 4% of all lung cancers, and there’s a good new drug that we think will work in it. Unless you have a broad-based screening trial like this, and you have multiple studies, you can’t achieve that goal, because no one wants to screen 100 patients to find only 4 who are eligible for a trial. And, a patient doesn’t want to be told, “Oh, you have a rare genotype; you have only a 1-in-a-100 or 4-in-a-100 chance of having it.” So, Lung-MAP is proving to be very successful, and I think it will continue for the longer-term future.

Q: When you say ‘very successful,’ what do you think are the most noteworthy results to come out of this project?

Gandara: When Lung-MAP was developed 5 years ago, it was really forward-thinking, I would say. Our goal was [to determine if] we could screen lung cancer patients for a variety of genomic mutations and alterations, in a fast, efficient manner, and then place them on to substudies where they would get a drug against that target-and the answer was yes, we could. Our average turnaround time for the FoundationOne test is 10 days. Clearly, that’s within the window of someone in the community using a test like this to screen their patient, unless, of course, it’s an emergency. We’ve shown that it’s feasible; we can screen, and we can do it in a timely fashion. The other thing is, we’ve already completed a dozen trials. Now, some of these were negative, but these are all drugs and mutations that are FDA approved in other cancers. What we showed in a very timely fashion was that the same mutation in a lung cancer patient wasn’t sensitive to the drug, even if it was, let’s say, in breast cancer or chronic lymphocytic leukemia or another malignancy, where these same drugs and targets led to FDA approvals. So, for all of these reasons, we can say that Lung-MAP has been successful.

It was also successful because we wanted to see if we could we engage all of the cooperative groups under the National Cancer Institute in Lung-MAP. And the answer was yes, with people from all the various groups leading various trials, leading various committees. We also said, Can we engage the community? And the answer again is yes. We have 650 sites throughout the United States. The majority are in the community, and the majority of accrual of patients to the trial has come from the community. So, another success story.

But we’ve had many challenges along the way. We’re writing a book. I’m just kidding. But we’re writing a book called Lessons Learned. When you try to put something together like this, it seems, of course, simpler on the surface than it actually is. Over the period of time we’ve been running Lung-MAP, we found that we had to make multiple adjustments, so we had to be flexible, nimble. For instance, after 1 year of the Lung-MAP, we had the approval of checkpoint immunotherapy in second-line treatment, and that changed everything. But it then gave us more opportunities to develop components of Lung-MAP, to say, “Well, what if a patient doesn’t respond to checkpoint immunotherapy, or what if they respond and then they fail?” So, we have an entire arm of Lung-MAP composed of trials for patients with immunotherapy-refractory disease.

Q: Let’s switch gears and talk a little bit about you and your career. Which of your investigative accomplishments are you most proud of?

Gandara: Well, I can start by saying that my particular interest has been in drug development, where I’ve had grants from the National Cancer Institute for 25 years for early therapeutics. One accomplishment I’m proud of is being a founding co-chair of the National Cancer Institute Investigational Drug Steering Committee, of which I am still a member. In addition, my interest in particular tumor types is lung cancer. I’m very proud to have led the lung cancer committee for the Southwest Oncology Group for 15 years, and in that regard, [to have had] many accomplishments associated with more than 100 clinical trials being accomplished through that group and through our association with the National Cancer Institute during that time.

I’ve also always considered myself to be an educator. So, I’m very proud that our ILCC is now in its 21st year. It is always among the highest-rated cancer conferences in terms of attendee ratings for the meeting, and that is quite an accomplishment. Additionally, we have a one-of-a-kind association in lung cancer, the International Association for the Study of Lung Cancer, and I am very proud to have not only led its world conference in San Francisco, but also to have served as the president of the organization. 

I think, lastly, I’ve always valued mentorship. When I had mentorship early in my career, that it was incredibly important to me, so I have tried to be a good mentor as well. At this point, I’ve mentored more than 50 young oncologists as well as PhD students and medical students, and I’m a mentor now to 5 different people on their grant submissions. A very important thing to me is being able to provide my expertise and my experience to help others.

Q: Are you particularly proud of working on specific drugs that have been brought to market?

Gandara: Well, I think probably the accomplishment I’m most proud of in terms of what I have developed is not a specific drug, but rather a test. A year and a half ago, I published for the first time an assay which could assess tumor mutational burden (TMB) from blood. This was in collaboration with Foundation Medicine and Roche Genentech, where we used a study on which I’m the senior author. The OAK trial, a positive trial for survival of atezolizumab versus docetaxel, is among my major accomplishments.

We went back to that trial and used blood specimens that had been collected to see if we could duplicate the predictive value that had been seen with tissue analysis of TMB, and, in fact, we could. That diagnostic test has now completed its phase 3 evaluation in a trial called BFAST. We don’t know the results yet, but it is a trial where atezolizumab or platinum chemotherapy were the 2 arms, and the patients were selected by blood TMB. So, I would say that is one of my greatest accomplishments, but I don’t know if we will have a companion diagnostic yet. It depends on the results of the trial.

Q: You’re pretty active on Twitter. How did that come about, and why?

Gandara: My interest in Twitter comes from 2 areas, I think. One is being an educator: If you’ve seen my tweets on Twitter, you know most of them are talking about breakthroughs or controversies, where I’m either providing information like the link to a publication, or I’m saying I thought this was quite impressive, what do you think, and engaging not only oncologists who are on Twitter, but patients and patient advocates. There is [also] so much bad information on the internet, I feel like it is part of my moral obligation to do what I can to speak on a factual basis, and to point it out misinformation. Communication with patients and patient advocates has been another aspect of my career that I have concentrated on. Some physicians have the skill to be able to break down complex information regarding genomics of cancer or treatment and describe it to patients in a way that they can understand. I’ve always worked on that skill, to the point where now I think I do a good job of it.

I’ve taken this into many venues. For example, the Addario Lung Cancer Foundation, now known as GO2 after their recent merger, has a monthly session called the Living Room. In their headquarters in the San Francisco Bay area, they have a big room with couches set up like a living room, and once a month they serve dinner and it is filled with patients, patient advocates, their families, and their friends-but it is also webcast live to 140 countries around the world. I have spoken there probably yearly, and among the things I’ve tried to do is to communicate to patients in ways that they can understand. I use a lot of analogies. For example, when you talk about genetic testing of cancer, and how many mutations there could be and why every lung cancer patient is different, I will hold up my finger and I will say, “You know that your fingerprint is different from essentially everyone else’s,” and everybody says yes. Then I tell them that when we’re talking about this molecular testing, this next-generation sequencing for hundreds of genes, that is the molecular fingerprint of your cancer. Then they say, oh, yeah, that makes total sense now, I understand this. Or I will talk about why a TKI against EGFR mutation works initially, and then it stops and there’s drug resistance. I will talk about the driver. I’ll say, “Pretend you’re on a bus, and you’re driving, and you stop at an intermediate stop and the driver gets off, and the person in the row behind him becomes the new driver. That’s what’s happening in your cancer. That’s acquired resistance. You have a new driver for your cancer, so we have to test and find out what it is and treat it appropriately.” So that is another communication skill that I feel is very important, and I try to share it when I can.

Q: I’ve read that you’ve always had an interest in writing. It’s somewhat unusual to see someone who combines a passion for science with the ability to write. How have you found that you can marry those 2 interests?

Gandara: I’ll give you a little background story here. When I graduated from high school, I said that I wanted to be a writer. I was going to be the next Hemingway. Once I got into college, I said, oh, Journalism 101, this doesn’t interest me so much-maybe I should look at something else. So, I decided to go into medicine. But I have always kept my interest in writing, and I think I actually have a fairly good writing skill. So, whereas other people sometimes struggle with putting their clinical studies or their research into manuscripts, I actually love to do it. I edit manuscripts for many, many other people. So, I have been able to blend my writing skills into my medical career. I’ve published almost 400 peer-reviewed articles and hope to do more.ν

Disclosures:

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.