Markman Reflects on Key Advances Made in 2023 in the Realm of Gynecologic Cancers and Beyond

Maurie Markman, MD

In an interview with OncLive®, Maurie Markman, MD, president of Medicine & Science at City of Hope, Atlanta, Chicago, Phoenix, highlighted inroads made with immunotherapy, antibody-dependent cytotoxic agents, and molecular testing across oncology. He also shed light on the evolution of care in gynecologic oncology, and where future efforts should be focused to continue to move the needle forward.

OncLive: Reflecting on this past year, if you could use one word to describe how you’ve seen the field advance over the past year, what would it be and why?

Markman: Revolutionary. I think the changes in therapy across the board have been monumental, in a positive way, for patients, as well as the complexity [that comes with that]. Obviously, our understanding of the molecular biology of cancer [has increased], and that is increasingly translating into meaningful therapeutics for patients. I don’t see any end in sight to this.

Definitely revolutionary. Looking at the entire gamut of oncology, what would you list as the top 3 biggest advances of the year?

It’s always hard to come up with that, although I do believe there are several things that stand out. Clearly, immunotherapy [is one of them]. Immunotherapy. Immunotherapy. Immunotherapy. That is not unique to 2023, but it’s an acceleration of what we’ve seen over the past 5 years and beyond. [We're seeing] increasing indications for immunotherapy, different immunotherapeutic strategies, and basically, novel ways to utilize the immune system to attack cancer. That’s [the] number one [advance].

Number two, and you [could even] say [that this is] number one [because it’s] a tsunami that’s coming, [but] the antibody-dependent cytotoxics. We’re [exploring the idea] that antibodies themselves are going to, in fact, not be used as the inhibitor itself, but really as a strategy to attach to a cytotoxic—[or] various cytotoxics—and depending on what the target is, then destroy the tumor. Increasingly, this is occurring in individual tumor types, but I think the real change is tumor agnostic. HER2 is a wonderful example; I think that’s going to be a sea change when we see tumor agnostics approved. But we’ve known that 1% to 3% of a variety of tumors have had overexpression of HER2. [We] have not been able to take advantage of that except in breast cancer and a few other tumor types, but it’s been there. The idea [that] an antibody that can get to those overexpressed cells within a particular tumor, deliver a payload, and produce a cytotoxic effect—we see that now, we see it very clearly in incredibly impressive trials. I anticipate broad-based approval for several such agents—again, an antibody attached to a cytotoxic— [and] that’s going to revolutionize our care.

But the final issue that we see in front of us—and as exciting as it is, it is beyond overwhelming for an oncologist—really relates to the true enormous amount of information that is out there now, particularly as it relates to molecular diagnostics [and] therapeutics that are absolutely dependent upon a particular molecular profiling. This includes not only somatic, but also germline, tumor-agnostic approvals, which are all highly relevant for the patient in question. It might be 1%, 2%, or 5% of patients, but it will not be thought of in and of itself because it’s not necessarily relevant to the particular tumor type. However, unless you do the testing, you will not think of the therapeutic, and if you don’t think of the therapeutic in that regard, patients can be harmed.

The amount of data is overwhelming. The decision support that is available is essentially nonexistent or woefully inadequate. How are we going to deal with that moving forward? How are we going to be able to prepare the oncology community—current oncologists and new oncologists [alike]—with the massive or beyond massive amount of data that is relevant for their patients from the point of view of molecular testing, the therapeutics, and how we [can] get those drugs to the patients with the complexities of our system. This is the [big] question, in my opinion, for 2024 and beyond.

You specialize in gynecologic oncology. In your opinion, where has the most progress been made over the past year in this arena?

The gynecologic cancer arena is obviously extraordinary. It is, [and has been,] my interest for decades. In the past, [the excitement] was [in] ovarian cancer—not only ovarian cancer from the point of view of gynecologic cancers, but obviously ovarian cancer as the paradigm for new drug development in solid tumors. The platinums, the taxanes, etc., came out of that research arena. And then, when you talked about endometrial cancer, [the thought was] was “Oh, whatever we use an ovarian cancer, we’re going to be using in endometrial cancer.” I mean, there might not have even been an approval, and certainly, there wasn’t interest [from] pharma [to look] at endometrial cancer. I mention that because we laugh now; the world has changed. Obviously, ovarian cancer [research] remain an incredibly exciting area. Again, [we have seen] new developments in the area of antibodies delivering cytotoxic payload. [This is] very exciting in ovarian cancer, and it will be true in other gynecologic tumors, as well.

But in endometrial cancer, it is a whole new world, and that world is immunotherapy. We’ve seen some recent results that demonstrate that the use of a checkpoint inhibitor plus chemotherapy as frontline therapy in metastatic endometrial cancer or recurrent endometrial cancer has truly phenomenal results, both from the point of view of PFS, and obviously early but clear data [as it relates to] survival. We are now moving [away] from, [but] not eliminating chemotherapy; immunotherapy [is] now becoming increasingly [utilized] up front in advanced endometrial cancer.

So, then the question will be, well, if it’s what we should be using in metastatic and recurrent disease—which in my opinion today, that is the case—then how about earlier? Should we be using it in patients with stage III disease, not as widespread as stage IV? I would argue very strongly that the answer that to that would be, “Yes.” I wouldn't suggest going earlier because the vast majority of patients with endometrial cancer, fortunately, are cured with surgery, surgery plus radiation. But when you get to the point that you’re talking about the need for systemic therapy, it is my belief that immunotherapy plus chemotherapy is the way to go.

Now, you can argue that’s really quite interesting, but there’s obviously the question of cost and the question of toxicities. So, I think it’ll be very important that we narrow down the population [for this]. Clearly, it’s across the board now in the data. We had talked about in the second-line setting, a microsatellite instability–high [MSI] population with endometrial cancer is much more likely to respond to checkpoint inhibitors than the proficient population. And that’s certainly true if you’re looking at single agents in the second-line setting. But again, the data appear really quite clear: When you’re using it in metastatic disease or recurrent disease, immunotherapy is more effective with chemotherapy in the MSI-deficient population, but the entire population benefits. That being said, that doesn’t tell us how best to target this therapy. If we can find ways of really knowing the population that is most likely to benefit and find a population that will not benefit—that doesn’t mean that we [will] abandon that population, it [just] means we [can] look for alternative approaches. But again, in endometrial cancer today, [the key advance is] clearly immunotherapy, immunotherapy plus chemotherapy, and a lot of new drugs that are being developed, as well.

We have an interesting issue from the perspective of drug development in endometrial cancer, which I’ll just briefly mention. One thing about immunotherapy is that we might give it for a couple of years…That gets into this concept of maintenance therapy. You say, “Well, what’s wrong with that?” Well, what’s wrong with that is nothing from a patient perspective; but from a drug development perspective, if you have a new product, a new drug coming along, [you’ll have questions.] You [might ask,] “Well, where would I try to get that into the paradigm? Where would I test it? Do I only test it in people who are now beyond 2 years, who have had immunotherapy [fail]? Do I somehow try to get it within the standard milieu that we use right now?” Obviously, there are a lot of questions to be answered. But the bottom line in endometrial cancer is that immunotherapy has had a major impact.

In cervical cancer, [there has been] slower development, but still major, major advances. Immunotherapy has become very important, and much more targeted here. Again, we have antibody cytotoxics being combined that have been positive. I think, again, we’ve made some real advances beyond the standard radiation, platinum. There is no question of the advances [made] there. They are not of the magnitude [seen in] endometrial or ovarian cancer, but we are moving in the right direction and it is all very exciting.