Recent Developments in Management of Gynecologic Cancers - Episode 10

Frontline Therapies for Metastatic Cervical Cancer


Bradley Monk, MD, FACOG, FACS: We talked about staging. We’ve talked about neoadjuvant chemotherapy; a randomized phase III trial that shows there’s no benefit here. We talked about the controversy between minimally invasive surgery. Let’s transition to metastatic disease. What is the standard treatment for first-line metastatic disease in cervical cancer?

Krishnansu S. Tewari, MD: Based on the GOG [Gynecologic Oncology Group] 240 trial, which was reported here at the ASCO [American Society of Clinical Oncology] Annual Meeting in 2013, chemotherapy doublets, platinum doublets—most commonly, cisplatin, paclitaxel with bevacizumab. Most or many oncologists are using carboplatin, and paclitaxel plus bevacizumab extrapolating from a Japanese study, JCOG0505, which showed significant noninferiority between the 2 platinum-based doublets. There was no bevacizumab in that study. Importantly, though, in subset analysis patients who are cisplatin-naïve, who never received it with radiotherapy, should probably stick with the cisplatin-paclitaxel-bevacizumab triplet for a first-line treatment of recurrence.

Bradley Monk, MD, FACOG, FACS: You and I worked hard on this as a collaboration. So frontline platinum paclitaxel, with or without BEV [bevacizumab], but try to get BEV in as long as there’s not a contraindication.

Krishnansu S. Tewari, MD: Right.

Bradley Monk, MD, FACOG, FACS: And counsel the patient. And if she’s cisplatin-naïve, maybe cisplatin rather than CARBO [carboplatin].

Krishnansu S. Tewari, MD: Right.

Bradley Monk, MD, FACOG, FACS: What’s the second-line standard, Dr Birrer, for metastatic cervical cancer?

Michael J. Birrer, MD, PhD: There is none, essentially. And it’s a dismal diagnosis, unfortunately. The bar is low there for the development of new and novel agents.

Bradley Monk, MD, FACOG, FACS: But we got an approval on June 12. Tell us about that June 12, 2018, approval.

Michael J. Birrer, MD, PhD: Using I/O [immuno-oncology] and PEMBRO [pembrolizumab] was approved in essentially viral-related HPV disease. It’s interesting because the response rates are not overwhelming, 14%. But those patients who respond, I think, do reasonably well with a long duration.

Bradley Monk, MD, FACOG, FACS: We have 2 other trials now they’re trying. Let’s talk about frontline. Back to you, Krish. Two trials that are trying to add atezolizumab to the platinum-taxane-BEV—4 drugs versus 3. Then obviously pembrolizumab also in that same setting—platinum, taxane, PEMBRO with or without BEV. We’re trying to do quadruplet therapy. Tell us about your study with cemiplimab second line.

Krishnansu S. Tewari, MD: Cemiplimab is an anti—PD-1 [programmed cell death protein 1] molecule. As you know, it was approved for cutaneous squamous cell carcinoma last year, and we’re studying in the second-line setting for patients who’ve progressed on platinum. They didn’t have to have bevacizumab up front, but they must have had to progress on platinum. And we’re looking to see if, in the second-line setting, a monotherapy I/O is going to be effective and tolerable.

Michael J. Birrer, MD, PhD: So platinum taxane and BEV frontline? Pembrolizumab accelerated approval second line, trying to show an OS [overall survival] benefit with cemiplimab second line, and then first line trying to quadruplet BEV I/O with chemotherapy. So that’s good. Jubilee, tell me about this TIL therapy, tumor-infiltrating lymphocyte therapy, and what’s happening in that space as a new investigational process.

Jubilee Brown, MD: This is really intriguing, actually. The concept is harvesting metastatic tumor, metastatic cervical cancer from a patient, and essentially preserving it, sending it so that it can be purified. And the TIL, the tumor-infiltrating lymphocyte, is magnified, and billions of cells are then transported back. Once the patient is immunosuppressed with chemotherapy, they have their infusion of TILs given, and then they’re followed up with IL-2. Dr Amir Anthony Jazaeri presented some of that data here and showed a 44% objective response rate.

Bradley Monk, MD, FACOG, FACS: Second-line cervical cancer, 44%.

Jubilee Brown, MD: Pretty amazing.

Bradley Monk, MD, FACOG, FACS: Take the TIL out, expand them, marrow-depleting chemotherapy, put them back, and stimulate.

Jubilee Brown, MD: Really intriguing.

Bradley Monk, MD, FACOG, FACS: You were talking to me about the breakthrough designation.

Michael J. Birrer, MD, PhD: Yeah. You know the FDA has a number of different sort of programs for agents that look interesting. Fast track is actually sort of the first. They got fast track, I think, in February, and that allows them to get access to the FDA and communicate with people. The next level up was a breakthrough, and they’ve gotten that. And that allows them actually to communicate with a very senior level in the FDA. I’m not sure that guarantees it will be successful therapy. What it means is that there are people who looked at this, and it’s quite exciting.

Bradley Monk, MD, FACOG, FACS: I think that’s very exciting.

Thomas Herzog, MD: Really innovative.

Bradley Monk, MD, FACOG, FACS: But it’s toxic, right?

Thomas Herzog, MD: It follows up with the data we’ve seen out of the NCI [National Cancer Institute], right?

Bradley Monk, MD, FACOG, FACS: The difference between this product is it’s scalable, and you can transport it across the country. The reason the initial trials were done at the NCI was because they had difficulty against shipping these TILs across the country, maybe even across the Atlantic Ocean. Now they have a preserved product that they can ship and they can even save, so you can actually give it again. It’s a great opportunity, and that’s really been the transformation and the science to make this scalable, reproducible, and an opportunity across the county.

Krish, that’s 1 experimental therapy. There’s another antibody drug conjugate. Tell us about that in cervical cancer.

Krishnansu S. Tewari, MD: Yeah. Polatuzumab vedotin is an antibody drug conjugate that targets the folic acid receptor.

Bradley Monk, MD, FACOG, FACS: Tissue.

Krishnansu S. Tewari, MD: I mean tissue factor. And a couple of years ago we had at the ESMO [European Society for Medical Oncology] Annual Meeting, it was reported and investigator assessed response in patients that had recurrent cervical cancer, 31% objective response. Just last year at the ESMO annual meeting there was an update using an independent radiology review, and those same 34 patients in that second review, response was 41%. Close to what we’re seeing with TILs, really exciting, and the drug is being studied with larger cohorts of patients right now.

Bradley Monk, MD, FACOG, FACS: Yeah. Dr Birrer said, “Oh, you know, recurrent cervical cancer is a very poor prognosis.” Tom said, “In ovarian cancer we’re getting lots of lines of therapy, and here we go.” I would really like this to be, someday, where patients can get multiple lines of chemotherapy. Chemotherapy and BEV, with or without I/O. They didn’t get I/O frontline, get I/O again, and then get an antibody drug conjugate. And then you have TIL on the table. Maybe we can, just like in ovarian cancer, do these PFS [progression-free survival] on top of PFS, and we can increase the prevalence, which is really increasing the survival.

Michael J. Birrer, MD, PhD: Right. And you add to that factor that this is a patient population that was fairly young. And probably in many ways healthier than ovarian cancer patients. They should be able to tolerate more regimens, including relatively toxic ones with TIL.

Thomas Herzog, MD: The 1 difficulty with these patients that present with advanced disease, and they’re the most likely to recur, is that they have radiation. And that changes things a little in terms of drug delivery, tissue bioavailability, and so forth.

Bradley Monk, MD, FACOG, FACS: And special populations, right? So low socioeconomic populations.

Thomas Herzog, MD: Socioeconomic factors to figure in terms of compliance and support for getting through these difficult and tedious therapies—you know, tedious schedules.

Michael J. Birrer, MD, PhD: And you wonder whether that plays into why the response rate to anti—PD-1 is only 14%. Does somehow radiation affect that? I don’t know the answer.

Thomas Herzog, MD: It’s just shocking. It should be higher.

Bradley Monk, MD, FACOG, FACS: Finally, we talked about TIL, antibody drug conjugates, and I/O. What about HER2 mutations? Tell us about those, Michael.

Michael J. Birrer, MD, PhD: Well, this is an example of how a study like TCGA [The Cancer Genome Atlas] really pays off. They sequenced a large number of cervical cancer patients’ tumors. And 5% of them have activating mutations in HER2. They’re mostly in adenocarcinoma. And you can target that. You can target that with a small-molecule inhibitor. It’s been done, and they’re seeing responses.

Bradley Monk, MD, FACOG, FACS: The biomarker world in cervical cancer is PD-L1 [programmed death-ligand 1], because if you have PD-L1, you may be able to respond. It’s mostly squamous tumors. And also HER2, where you might be able to get a tyrosine kinase inhibitor, and that’s mostly adenocarcinoma.

Michael J. Birrer, MD, PhD: Yeah.

Bradley Monk, MD, FACOG, FACS: Those are the 2 validated biomarkers in cervical cancer.

Transcript Edited for Clarity