Tripathy Details Importance of Both Clinical Research and Patient Advocacy

Oncology, ONCOLOGY Vol 36, Issue 1, Volume 36, Issue 2
Pages: 13-15

“If we can understand the mechanisms of resistance to be able to monitor [patients] in real time, then we will be able to turn many cases of cancer into chronic diseases.”

With the approval of trastuzumab (Herceptin) in the 1990’s, targeted therapy became an option for treating patients with HER2-positive breast cancer. And as technology for systemic therapies evolve, new treatments continue to emerge for these patients.

In an interview with ONCOLOGY®, Debu Tripathy, MD, discussed his involvement in the first pivotal trial of trastuzumab and, since then, his participation in other advancements in breast cancer. He explained how his upbringing influenced him to choose this career path, and his involvement in breast cancer patient advocacy.

Tripathy also recalled the patient stories that have touched his life, and how he admires the courage they hold when dealing with cancer. He also discussed ongoing trials in the breast cancer space, how the treatment of brain metastases are evolving for women with breast cancer, and current trends that have the potential to impact this disease state.

Q:What inspired you to become an oncologist, specifically for breast cancer?

A: I had several different initial motivations. When I was young, I was very interested in science and experiments, and learning about physics and biology. It just seemed natural that I would want to go in that direction. Of course, my father was also a physician, and he was a laboratory researcher as well. When I was young, [about] 8 to 10 years old, I used to go to the lab and help wash the glassware. I was fascinated with all the experiments that they had going on, and I used to go on house calls with my father where I got to see the whole picture, and I was very fascinated with it. That that was my first entry [into the medical world].

When I went into medicine and understood what it was to be both a researcher and a physician, I got very involved in the breast cancer advocacy movement. I worked with a lot of patient advocates that wanted to get involved in some of our research activities, but also developed models of patient-centered care. Around that time, electronic medical records were being developed, so I got involved in projects that were more on the patient-centered side of both patient care and research. I found that to be a well-rounded way to approach any profession, [because] I didn’t want to be trapped in just the cold science part, or [have] a super busy clinician type of experience either. To me, what I was doing just seemed to be the best fit, so I came to it from both those angles.

Q: Has there been any clinical research that you’re most proud of?

A: Very early in my career, I was fortunate to have been involved in a very interesting translational project. When I was a fellow at UCSF [University of California, San Francisco] in the mid- to late-1980s, I got [to participate in] a project to turn off this new oncogene that had been discovered recently called HER2, or human epidermal growth factor receptor. My job in the lab was to turn it off using antisense DNA. As a control, I needed to have a good antibody that worked. [I knew people,] from Genentech, [who] gave me this antibody that turned out to be Herceptin [trastuzumab]. Of course, it wasn’t called that at the time.

We started doing studies with it and eventually, myself and a couple of other investigators around the country, started to do early-phase clinical trials. We talked Genentech intogetting that antibody moved into [our] clinic, which they didn’t want to do initially. I got to be involved in the phase 1, and ultimately the phase 2, Herceptin studies, and it was 25 years ago that our first publication on Herceptin came out.1 That was one of the first targeted therapies, and I was fortunate to be involved in that very early in my career. I was a fellow going on to junior faculty, and then I got to be one of the 3 physicians that presented the data to the FDA when it got approved in 1998.2 That was a special accomplishment, and I’ve been fortunate enough to continue to be involved in some of the newer targeted therapies.

More recently, I was involved in the CDK4/6 agent trial with ribociclib [Kisqali],3 which was the first one for premenopausal patients. I was the global principal investigator of that trial, and it was also the first one to show a survival advantage [over endocrine therapy alone in the hormone receptor–positive, HER2-negative setting]. We were excited when those data came out because we had broken the survival barrier that really hadn’t been crossed in HER2-negative breast cancer. Being part of that story was very exciting, but I would say that these kinds of victories mean much more when you have patients that are on these treatments, as well as when you’re working with a great bunch of scientists where you’re still trying to push the envelope. Right now, we’re involved in trying to
understand why patients become resistant to CDK4/6 inhibitors, and we’ve come across one pathway for which a new drug has been developed. We just got grant funding to now open a trial to test that [agent] in patients who have become resistant to CDK4/6 inhibitors. Those are a couple of examples that are energizing and exciting.

Q: Have there been any notable patient cases that have stuck out to you over the years?

A: This goes back to the old early days of working with Herceptin, I saw a patient who barely qualified for the Herceptin trial because she had a lot of liver involvement with metastatic breast cancer. Her liver function tests were just borderline to be able to go on to the study; she did make it but she had a rough time. She got sicker initially, but then improved and I finally cleared her to go on vacation. She sent me this amazing picture of her scuba diving in Belize, and I had remembered just a couple of months before that she was so ill that I didn’t think she would even qualify for the study. Seeing someone send me a picture from vacation, that was a special moment.

I’ve always been very communicative with my patients. I call them a lot; I stay in touch with them, and I also return their calls. I’ve been fortunate enough that I don’t have 3 days of clinic a week or 4 days of clinic a week. I’ve always had either 1 or 2 days of clinic and kept time for research so that my clinic loads have not been overwhelming. I really sympathize [with] physicians that have super busy clinical loads, because it’s hard to maintain that personal touch with patients, but I have always been mindful of what my patients are going through.

Q: Are you currently involved with any exciting trials or are there any you’re excited about?

A: I’m involved in a couple of trials, one of the more exciting ones is looking at the evolution of genetic alterations in patients through blood tests and identifying new mutations as they arise to adapt our treatment for patients. We have a study that is focusing on one specific mutation called ESR1.

What’s exciting about it is that, to me, it seems like the new order of things to come where we are monitoring what is a dynamic state. Just like rivers continue to flow and form the landscape, we know that tumors do that, too. They are in continual evolution, and we have better and better tools to measure exactly what’s going on and what new mutations are being acquired to understand how that cancer is surviving. It’s adapting to do what it does, and if we can stay one step ahead of it and understand those dynamics, be able to interpret the blood tests, and then fashion a personalized treatment accordingly, we can ultimately be able to decipher what most cancers do to become resistant to drugs.

We often have a drug that works for a patient, but the problem is they become resistant at some point. If we can understand the mechanisms of resistance to be able to monitor them in real time, then we will be able to turn many cases of cancer into chronic diseases [for people who are] doing well in terms of their quality of life. Of course, we have a long way to go to get there. But every day we are understanding more not only about the genomics, but what the consequences of those genomic alterations are so we can develop newer treatments and essentially adapt as patients do in real life. We’ve already done that with some diseases, [such as] leukemias, where they can be monitored and the treatment is adapted. For the more common solid tumors, like breast and lung, we’re a little further behind, but I have every hope and expectation that we will catch up and be treating patients in the same way.

Q: Looking ahead, are there any approvals that might be practice changing in breast cancer treatment?

A: There’s some interesting work in immunology to understand how to make cancer cells more immunogenic. That’s an important area that we’re working on. There are signaling pathways such as the aKP pathway, which is an area that we’re going to be hearing about, and some key trials are going to be coming out in those areas.

Q: Can you go into more detail about some of those trials?

A: Well, one of them is a follow up of a trial that is an NCI-MATCH trial targeting AKT [NCT02465060]. There’s another study called the FAKTION study [NCT01992952] that’s looking at the role of AKT, which is a signal transduction pathway. Another area that is interesting is that we’re part of a collaboration to target HER2-low cancers. Targeting HER2-positive cancers with Herceptin was a real revolution, but we’re finding out that many cancer cells that we have traditionally called HER2-negative still [express] a small amount of HER2. One of the questions is, can we treat patients with low HER2 if we have powerful enough drugs. Enhertu [trastuzumab deruxtecan] was a recently approved drug for HER2-positive cancers.4 That’s probably one of the most potent drugs we have against HER2 cancers. It turns out that that may also work in HER2-lower cancer. The
results of the HER2 low trial are probably going to be coming out later this year.

Q: What are your thoughts regarding the changing landscape for management of brain metastases in women with breast cancer?

A: We certainly have drugs now that work against brain metastases without having to use radiation. When patients have brain metastases, they also have metastases in other parts of their body. If we can treat them with a single regimen that treats both their tumors in other parts of the body as well as the brain, that’s a big step forward. There has traditionally been the blood-brain barrier that keeps toxins out of our brain for reasons of protecting the brain. When people [receive] certain drugs, it’s a problem because the drugs don’t get into the brain. That can be a place where there is seeding going on and brain tumors can grow because the drugs can’t get there. However, some of the newer drugs are able to get [past] the blood-brain barrier, and they’re potent enough that they have activity there.

Some of the newer drugs that have been approved for breast cancer seem to have brain activity, and these patients can have responses and live a long time. We’re at the point now where people with brain metastases can live for years. Now, the next barrier to cross is going to be treating non–HER2-positive brain metastases, and there are some newer agentsthat are being looked at that may have an impact in that area as well. It’s still early, but I think that we’re starting to make a difference in patients who have brain metastases, as well as those in other areas.

There’s another drug called sacituzumab govitecan also known as Trodelvy that was recently approved, and that may also have some activity in the brain. That’s another area where we expect patients to live longer and longer and do better and better. Believe it or not, the cost of developing some of these drugs and getting them into the trials is going down. We can now do trials for rare groups of patients, and that’s another trend that has been very welcome. With some of these genomic abnormalities and mutations that are very uncommon, we now have drugs that work for cancers that are very rare. They may be a common type of cancer but only a fraction of them has that mutation, so it makes it essentially a rare cancer.

Q: If a patient has a certain tumor type, will they be matched across all solid tumors?

A: It’s happening more and more, but it doesn’t always work. Sometimes, the same mutation and a different tumor may not respond as well to a drug. In many cases, it does. We don’t know until we test it. Now that we’re doing much more common genomic testing, we’re starting to develop what are called basket trials, and these are trials where you can enroll someone with any tumor type if it has a mutation. Some drugs have been approved that way. There are some rare mutations in breast cancer, for example, called the NTRK1 mutations, and these are more common than other cancers, but there’s a couple of drugs now that are approved for them. We’re sequencing everyone, because we may find a rare mutation that’s got a drug approved for it, regardless of where that came from.

REFERENCES

1. Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14(3):737-744. doi:10.1200/JCO.1996.14.3.737

2. Trastuzumab, Package insert. Genentech; 1998, revised 2010. Accessed November 16, 2021. https://bit.ly/3wQ1UbD

3. Im SA, Lu YS, Bardia A, et al. Overall survival with ribociclib plus endocrine therapy in breast cancer. N Engl J Med. 2019;381(4):307-316. doi:10.1056/NEJMoa1903765

4. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. US Food and Drug Administration. December 20, 2019. Accessed November 18, 2021. https://bit.ly/3HALwk7