David O'Malley, MD

 When we talk about adverse events with I/O [immuno-oncology] therapy, it’s important to have a high degree of suspicion. This isn’t just checking the CBC [complete blood count] and making sure their ANC [absolute neutrophil count] is OK. Obviously, we have a high degree of suspicion with pneumonitis. We don’t have a blood test for pneumonitis. We also consider colitis, making sure we’re asking them if they’re having diarrhea. It’s important to think about the endocrinopathies that will also sometimes present with vague symptoms or frontal headache, severe fatigue, and maybe even present like sepsis. You have to think about it at any point during therapy.

How does that contrast to the adverse effects of tisotumab vedotin? TV [tisotumab vedotin] is an antibody-drug conjugate. When we look at the 3 main toxicities of TV [tisotumab vedotin], No. 1 is eye toxicity. No. 2 is bleeding, but it’s really just epistaxis. It’s not dangerous bleeding, but it can be annoying epistaxis. And third is neuropathy, with the payload of antimicrotubulin that we see some neuropathy. Manage that as you manage neuropathy with paclitaxel.

However, a new toxicity that some of us have seen is eye toxicity with TV [tisotumab vedotin]. The eye toxicity can be mitigated by using interventions proactively. What are some of the things? We tell patients, “Don’t do things that are going to irritate your conjunctiva.” Avoid wearing contact lenses. Use lubricating eye drops throughout the entire process. Around the time of the infusion, use steroid eye drops as well as constrictors to minimize the delivery to the conjunctiva. We also do eye packs over the eyes. That has the same rationale. If you have a patient who develops conjunctivitis, make sure you have partnered with an ophthalmologist who can help you treat these symptoms. The mitigation strategies have significantly decreased the occurrence of grade 3 or higher conjunctivitis. But they can continue to be a low-grade process, which can be drastically mitigated by partnering with an ophthalmologist.

The future of recurrent cervical cancer and treatment revolves around improving the chance for curative intent. One of the best ways to do that is through dual blockade from an immune standpoint. We also have other drugs being developed that are exciting with regard to molecular basis and antibody-drug conjugates. It’s so important for us to enroll these patients on clinical trials if that’s an option. We need to move the field forward as we’ve done over the last 10 years and continue to see improvements in not only how long patients are living but also their quality of life, potentially increasing curative intent.

My advice for the treatment of women with recurrent or metastatic cervical cancer is to use your best therapies up front. We know that when we utilize our best therapies—platinum doublets, antivascular therapy with bevacizumab, immunotherapy with pembrolizumab—patients do better and live longer. And this is in randomized controlled trials. Obviously, PD-L1 testing continues to be important. The option for first-line therapy to add pembrolizumab to your treatment regimen of platinum doublet plus bevacizumab are for those who have a CPS [combined positive score] score of 1 or higher. It’s very important to check the PD-L1 status right away.

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David M. O’Malley, MD, discusses the management of adverse events across various regimens for cervical cancer treatment and provides insight on future directions for disease management.

Managing Adverse Events in Cervical Cancer Treatment

 As we look at this next generation of cervical cancer therapy, immunotherapy is the key moving forward, and combination immunotherapy is so important. Should it be a PD-1 inhibitor plus the CTLA4, LAG3, or TIGIT? I hope we explore all 3 dual-blockade options. An interesting agent is tiragolumab, which is a TIGIT antibody, most recently combined with PD-1 inhibitor atezolizumab. The SKYSCRAPER-04 trial has completed enrolling patients with previously treated recurrent cervical cancer. I hope we’ll see those results shortly. Once again, dual blockade is key in moving the field forward, potentially curing more patients.

Another agent on the horizon for the treatment of recurrent cervical cancer is cemiplimab. We’ve recently seen the EMPOWER-Lung 1 trial reported. In EMPOWER, we had patients who had previously been treated with a platinum doublet with or without bevacizumab then randomized to cemiplimab, a PD-1 inhibitor, vs physician’s choice, 1 of 5 agents. We found that there’s overall and progression-free survival benefit of cemiplimab. We hope to bring this agent into our armamentarium of therapies, moving beyond just pembrolizumab. What did this trial show me? It reiterated that if we have patients who haven’t previously received I/O [immuno-oncology] therapy in the first line, those patients’ first option should be to move to an I/O PD-1 inhibitor. It’s important in our opportunities to have sustained, durable responses in our patients with recurrent cervical cancer.

I can’t believe that I have the opportunity to talk about sequencing patients with recurrent cervical cancer and metastatic cervical cancer. What an amazing opportunity in the last 5 years. Clearly, in my mind, patients with recurrent metastatic disease should be offered the best therapies available, meaning a platinum doublet—carboplatin or cisplatin, depending on their prior therapies—plus paclitaxel combined with bevacizumab, the antivascular therapy, combined in the first-line setting with pembrolizumab. In those patients, we’re seeing additive benefits without additional toxicities. We need to use our best therapies in our first-line setting. Many of our patients might not have had an eye on the up-front setting.

In the second-line setting, my first option is an I/O treatment. Pembrolizumab is approved, and we suspect we’ll see cemiplimab. Clearly the first choice for all these patients should be clinical trial. What else do we have available? We have 4 or 5 agents that we can use that aren’t exciting, but we do have 1 exciting agent that’s just been approved: tisotumab vedotin. If I had to say tisotumab vedotin all day, I’d be in trouble, so I’m going to call it TV [tisotumab vedotin]. Many of us are calling it TV [tisotumab vedotin]. Response rates are between 25% and 30% as a single agent. If they’ve had previous I/O, my next choice is TV [tisotumab vedotin]. After that, you can pick 1 of 4 to 5 agents. The overall response rate is in the single digits, less than 10%.

Dr David M. O’Malley comments on emerging agents in the pipeline for the treatment of recurrent/metastatic cervical cancer and shares his approach to the sequencing of therapies.

Novel Agents for the Treatment of Cervical Cancer

 At the most recent SITC [Society for Immunotherapy of Cancer Annual Meeting], Agenus presented their AGEN1181. This is the next-generation CTLA4 with an Fc-enhanced region, which appears to have very nice efficacy when looking across solid tumors. The trial presented was an escalation into an expansion cohort across solid tumors, and they enrolled 116 patients. Solid tumors included colorectal, ovary, hepatocellular, angiosarcoma, pancreatic, and other.

A third of these patients had a previous I/O [immuno-oncology] therapy, and over half had 3 or more prior therapies. It was a very heavily pretreated population. In the escalation phase, they enrolled the AGEN1181 as a single agent, and then in the expansion, the AGEN1181 was combined with balstilimab, their PD-1 inhibitor. We saw some very interesting results. For example, of the 9 patients with ovarian cancer, 3 had confirmed partial responses. All 3 patients with microsatellite stable endometrial cancer had a confirmed response, 1 of those being a complete response. The efficacy is very interesting, but it’s very early.

Most important, with the CTLA4 inhibitors, we were worried about toxicity. The toxicity’s safety set was 100 patients, and they saw very reasonable immune-associated toxicity. With most CTLA4 inhibitors, the greatest question is on the colitis as well as endocrinopathies. It’s quite reasonable, but it did approach 11% for grade 3 or higher diarrhea and colitis. The immune toxicities seem to be less than has been previously reported with other CTLA4 inhibitors. This very interesting next generation of CTLA4, AGEN1181, showed some interesting clinical activity, both as a monotherapy and in combination. And once again, we saw this durability of response, so we hope to see this agent move forward, potentially as a single agent and in combination with balstilimab.

David M. O’Malley, MD, shares insight on data presented at SITC 2021 on the use of a second-generation, Fc-enhanced anti-CTLA4 antibody, AGEN1181, in patients with advanced cervical cancer as well as other solid tumors.

SITC 2021 Updates for Cervical Cancer: AGEN1181

 At this past ESMO [European Society for Medical Oncology Congress], I had the honor of presenting the single-arm trial with balstilimab, the PD-1 inhibitor, and zalifrelimab, a CTLA4 inhibitor, in patients with recurrent progressive or metastatic cervical cancer who had previously been treated with a platinum doublet with or without bevacizumab. We found in that trial that the efficacy was modestly improved over the single-agent balstilimab with a 26% overall response rate and, very interestingly, a 33% response rate in the PD-L1 positive patients.

The other part that I’m so excited about is that the complete response rate in the entire population approached 9%. With this combination of the PD-1 inhibitor plus CTLA4 inhibitor, we’re seeing modest improvements in the efficacy. We’re also seeing significant durability of response where duration response wasn’t met, and potentially patients who are having complete responses. We don’t know yet, but it’s possible that in second-line cervical cancer, patients with recurrent cervical cancer could be cured of their disease in the second-line setting. These results have led to the design of a randomized phase 2 trial, GOG-3028, or the RaPiDS study. It’s a 2-arm trial with balstilimab, the PD-1 inhibitor, vs balstilimab and zalifrelimab, the CTLA4 inhibitor. That’s ongoing and enrolling. For patients who haven’t had a prior immunotherapy, this is the trial I’d strongly encourage you consider.

Dr David M. O’Malley reviews ESMO 2021 updates evaluating the use of combination anti-PD-1 and anti-CTLA4 agents for recurrent and metastatic cervical cancer.

Recent Data on Use of Checkpoint Inhibitors for Cervical Cancer

 The percentage of patients who are going to relapse after primary therapy depends on the risk factors. Patients who have high periaortic lymph node involvement and locoregional disease are at much higher risk of relapsing, exceeding probably 40%. Those who present with advanced metastatic disease are essentially at 100% risk of relapse. For patients who have previously received or who haven’t received a previous immunotherapy, when they have the opportunity, I’m going to utilize an immunotherapy for the recurrent or second-line setting. If a patient hadn’t previously received a platinum doublet to include carboplatin or cisplatin plus paclitaxel with or without bevacizumab, that would be my first choice. Typically, most locoregional cancers will recur in the first 2 to 3 years.

We recently published the single-arm balstilimab trial on patients with recurrent persistent or metastatic cervical cancer. In that publication in 

, the PD-L1 inhibitor balstilimab showed an overall response rate of 15%, and the PD-L1–positive population response rate was 20%. But interestingly, in the PD-L1–negative population, we saw an 8% response rate. Clearly, this activity is similar to pembrolizumab and cemiplimab. At this point, though, balstilimab isn’t pursuing an accelerated approval in advanced recurrent cervical cancer, but it continues to be an option in combining with zalifrelimab.

The rationale for combining PD-1 inhibitors and CTLA4 inhibitors in cervical cancer speaks to the importance of potentially these synergistic—maybe synergistic is overstated—these 2 separate mechanisms of action. We’re removing the blockers of the immune response with the PD-1 inhibitors, and then we’re getting those tired T lymphocytes with the CTLA4 and we’re bringing more T lymphocytes into the immune response. The combination of PD-1 inhibitors and CTLA4 inhibitors and this dual blockade makes much more sense to give us the best opportunity for 1 overall response, and most important, sustained and durable responses with a dual blockade.

An expert gynecologic oncologist discusses the rationale for using PD-L1 inhibitors and CTLA4 inhibitors in gynecologic cancers.

Role of Anti–PD-1 and Anti-CTLA4 Agents in Cervical Cancer

 The cervical cancer landscape has drastically changed over the last decade or 2. We now have vaccinations. Like any vaccination, it’s not perfect, but we need to start thinking about it as a cancer prevention shot rather than a vaccination. What about our treatment of recurrent cervical cancer? We still have about 14,000 cases in the United States, and over 4000 women die each year. Yes, cervical cancer is a worldwide problem, but it’s not just a worldwide problem. It’s still a problem in the United States.

Not that long ago, we were talking about an overall survival of 7 to 9 months with recurrent or advanced cervical cancer. We’ve moved from platinum-based therapy or other alkylating agents, showing that the backbone is platinum plus a taxane. GOG-0240 showed us the efficacy of antivascular therapy with bevacizumab, which is now getting close to an overall survival of 2 years. KEYNOTE-826 has shown that we may be curing women with recurrent and advanced cervical cancer with the utilization of immunotherapy. In less than 10 years, we’ve gone from less than a year to live to potentially curative intent.

The systemic treatment options for recurrent and advanced cervical cancer focus around the backbone of platinum and paclitaxel. We know over time that these are the 2 best cytotoxic agents. GOG-0240 showed us the advantage of antivascular therapy with patients who have advanced cervical cancer. Most recently, we’ve seen the advantage of the utilization of immunotherapy in patients with advanced recurrent cancer. We also need to consider those with locally advanced or locoregional disease. Clearly, the backbone is radiation plus cisplatin therapy. But multiple ongoing trials are looking at the utilization of immunotherapy in addition to these, remembering that most patients with recurrent cervical cancer—approximately 85%—will have had locoregional disease to start with.

What factors do I consider while looking at a patient with recurrent and advanced cervical cancer? Obviously, their performance status. But if we have a young patient, even with a compromised performance status, we’re going to continue to be aggressive with cytotoxic therapy. With antivascular bevacizumab being the best therapy and showing survival advantage, I’m going to utilize bevacizumab unless there’s a strong contraindication, like uncontrolled hypertension, which you should be able to control, or recent DVT [deep vein thrombosis]. Even in that situation, if those patients are anticoagulated, I’ll use bevacizumab. It does somewhat come with a risk of increased fistulization rate, particularly for patients who have had prior chemotherapy-radiation and have a centralized recurrence. It’s important to discuss this with the patients so they understand the risk, knowing that they may have a higher risk of fistulization. But when I talk to them about the survival advantage, most patients are going to utilize bevacizumab.

For indication, we’ll talk more about KEYNOTE-826. But it’s important that utilization of pembrolizumab in the up-front setting has shown additive response rates exceeding 70%. In addition, we’re seeing patients with overall survival advantage with the utilization of pembrolizumab. Even though this wasn’t a preplanned analysis of patients who are PD-L1–negative, the FDA elected not to approve it for those who are PD-L1–negative, defined as CPS [combined positive score] less than 1%. So patients who are PD-L1–negative won’t have the opportunity to utilize pembrolizumab in the up-front setting.

David M. O’Malley, MD, provides insight on the evolution of cervical cancer and reviews current systemic treatment options for recurrent and advanced disease.

David O'Malley, MD | Authors

Articles

Managing Adverse Events in Cervical Cancer Treatment

Novel Agents for the Treatment of Cervical Cancer

SITC 2021 Updates for Cervical Cancer: AGEN1181

Recent Data on Use of Checkpoint Inhibitors for Cervical Cancer

Role of Anti–PD-1 and Anti-CTLA4 Agents in Cervical Cancer

Systemic Treatment of Metastatic/Recurrent Cervical Cancer