Doublet Therapy Remains Central to First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma
Clinical Summary:
- Stephanie Berg, DO, examines first-line treatment selection for patients with metastatic clear cell renal cell carcinoma, including the use of dual immune checkpoint inhibition and immunotherapy plus tyrosine kinase inhibitor combinations.
- Multiple first-line doublets offer clinical benefit, with treatment selection guided by disease burden, comorbidities, toxicity profiles, and patient preferences, while recent trials have not demonstrated an overall survival advantage with triplet regimens.
- These developments reinforce the importance of individualized first-line treatment selection and highlight expanding second-line options, including belzutifan plus lenvatinib, for patients with metastatic clear cell renal cell carcinoma.
Stephanie Berg, DO, Dana-Farber Cancer Institute, Boston, Massachusetts, discusses the evolving first-line treatment landscape for patients with metastatic clear cell renal cell carcinoma and the clinical considerations guiding treatment selection following her presentation at Great Debates in Solid Tumors in New York, New York.
Dr Berg reviews the trade-offs between dual immune checkpoint inhibition and immunotherapy plus tyrosine kinase inhibitor combinations, emphasizing the importance of disease burden, comorbidities, and treatment-related toxicity. She also discusses why doublet therapy remains central to first-line management and how emerging second-line combinations, including belzutifan plus lenvatinib, are expanding treatment options following disease progression.
Transcript:
Hello, my name is Stephanie Berg. I'm a medical oncologist at the Dana-Farber Cancer Institute for the Lank Center of Genitourinary Oncology. I'm here at the Great Debates meeting in New York City to talk about first-line treatment options for metastatic clear cell kidney cancer.
As we know, we have four FDA-approved options right now: ipilimumab and nivolumab, lenvatinib and pembrolizumab, axitinib and pembrolizumab, and nivolumab and cabozantinib for our patients that are diagnosed. I think as a clinician, there are key trade-offs that we need to think about between using the doublet immunotherapy like ipilimumab and nivolumab versus the other three combination therapies.
Something I always talk to my patients about is toxicity and how we manage the side effects. I think that's one of the very important things because a lot of the oral therapies are similar in that aspect, about causing high blood pressure, skin rash, fatigue, and decreased appetite. However, with the doublet immunotherapy, we have to think about, do they have enough reserve to have an immune-related adverse event– because it can happen in upwards of 30% of patients, specifically from the ipilimumab. So it's something I think about, too, when I look at their disease burden when they're diagnosed.
We know there's a big difference in patients that can be diagnosed with a high-volume disease burden with clear cell kidney cancer, or they had kidney cancer perhaps 10 years ago, and they come into your office and they have one small pulmonary metastasis or a pancreas metastasis, and we can use other techniques like surgery or radiation to treat their cancer and not really have to put them on systemic therapy, as I just discussed. So there's definitely a lot of things that we do in our consults and our day-to-day and how we counsel patients.
We know all of these therapies, though, have overall survival benefit, they all have progression-free survival benefit. So using those types of modalities between patients and how we care for them is really important.
I think a framework to do is when you take your individual patient, if you don't have a clinical trial option, as someone who works at Dana-Farber, we do offer clinical trials for all of our patients with kidney cancer, really go through with them these pros and cons of each treatment. I don't think there is a wrong answer, but there is something where, when you start the treatment, we know that first-line treatment is something so important because primary refractory disease after first-line treatment, patients are left with less options. So giving them the best choice up front based on their comorbidities, their disease burden, and what toxicity they can tolerate is really important.
I would like to say in kidney cancer, we are not quite there yet with triple combination therapies. We have not had any improvement in overall survival. There is new data that's coming out at ESMO called LITESPARK-012, which again has not shown improvement with triple therapies compared to another trial called COSMIC-313, where we did ipilimumab, nivolumab, and cabozantinib, and now again a negative trial with pembrolizumab, lenvatinib, and belzutifan. So doublets are here to stay, doublet immunotherapies are here to stay for right now, so please take those into consideration when you're talking with your patient and what really fits best for them.
Recently, the FDA has given approval for a second-line therapy called belzutifan based off the LITESPARK-011 trial. This was compared to cabozantinib. This showed an improvement in progression-free survival (PFS) and response rate, but not yet overall survival. We in the field are extremely excited about this combination therapy, specifically for patients who can tolerate a doublet therapy, because we know that belzutifan has really revolutionized kidney cancer treatment for the later lines of therapy, not only for its tolerability outside of known on-target effects like hypoxia and anemia, but that it is what we call a biomarker-directed disease against VHL, and patients really can respond to it.
So combining it as a second-line therapy with proven benefit after first-line therapy is really important, because now we can go from a doublet to another doublet and really improve survival, which, as I stated before, when you have refractory disease in the second line of kidney cancer, having meaningful benefits of PFS are extremely important for our patients. This was a great thing to see, and I believe the final paper is going to be published soon in the Annals of Oncology.
