David F. McDermott, MD

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses the promise of single-agent pembrolizumab (Keytruda) in the treatment of patients with advanced non—clear cell renal cell carcinoma (RCC).

In findings from cohort B of the phase II KEYNOTE-427 study presented at the 2019 Genitourinary Cancers Symposium, pembrolizumab appeared to be safe. Only 6% of patients had to stop therapy due to a treatment-related adverse event. This is important because there are currently no FDA-approved therapies specifically for patients with non—clear cell RCC. The National Comprehensive Cancer Network guidelines recommend sunitinib (Sutent), but even the VEGF TKI is not indicated for this subgroup.

In fact, McDermott adds, prior immunotherapy trials in RCC have excluded patients with non—clear cell histology. The PD-1 inhibitor yielded a 24.8% response rate in the entire cohort of patients with non-clear cell RCC, giving researchers a reason to continue evaluating the drug’s benefit in this space.

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David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses the promise of single-agent pembrolizumab in advanced non–clear cell renal cell carcinoma.

Dr. McDermott on the Promise of Pembrolizumab in Non-Clear Cell RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses single-agent versus combination immunotherapy in the treatment of patients with renal cell carcinoma (RCC).

At the 2019 Genitourinary Cancers Symposium, there was a lot of interest in the studies looking at immunotherapy plus VEGF TKI combinations, but McDermott says the benefit of those combinations is mostly driven by PD-1 inhibition. Generally, single-agent checkpoint inhibition is a better-tolerated therapy for patients, so a question moving forward is whether researchers can identify a patient subset that will derive benefit from this approach versus others. However, the field is still a long way from that.

Combinations such as pembrolizumab (Keytruda) plus axitinib (Inlyta), which was evaluated in the KEYNOTE-426 trial, are also fairly well tolerated, but they add complexity, specifically in dealing with chronic adverse events associated with anti-VEGF therapy. CheckMate-214 introduced nivolumab (Opdivo) plus ipilimumab (Yervoy) as a very encouraging frontline option for patients with metastatic RCC, showing impressive response rates and opportunity for patients to go into remission. However, McDermott says it is crucial for providers to understand the unique toxicities of combining PD-1 and CTLA-4 inhibitors.

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses single-agent versus combination immunotherapy in the treatment of patients with renal cell carcinoma.

Dr. McDermott on Single-Agent Versus Combination Immunotherapy in RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses the use of single-agent pembrolizumab (Keytruda) in the treatment of patients with advanced non—clear cell renal cell carcinoma (RCC).

At the 2019 Genitourinary Cancers Symposium, there was a lot of excitement about data with combination immunotherapy and TKIs. However, little is known about single-agent PD-1 inhibitors in previously untreated patients, McDermott says, and so the KEYNOTE-427 trial was designed to address this unanswered question. At the 2018 ASCO Annual Meeting, investigators presented data with single-agent pembrolizumab in patients with clear cell RCC, which showed a 36% response rate and good tolerability.

This year, investigators presented data regarding the agent’s use in patients with non—clear cell renal cell carcinoma, said McDermott. Most of these patients had papillary disease, and there were some with chromophobe disease or unclassified histology. The response rate in the overall population was 25%, McDermott says, which was better than what the investigators had expected. Response rate was also 25% in the papillary group, 10% in the chromophobe group, and 34% in the unclassified group. Interestingly, for the patients who were PD-L1–high, the response rate was 30% compared with 10% in the PD-L1–low group, suggesting that PD-L1 status may be a way of enriching response to pembrolizumab.

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses single-agent pembrolizumab in the treatment of patients with advanced renal cell carcinoma.

Dr. McDermott on Single-Agent Pembrolizumab in Advanced RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses an analysis of the CheckMate-214 study in advanced renal cell carcinoma (RCC).

Findings from the CheckMate-214 trial showed that frontline treatment with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) reduced the risk of death by 32% compared with sunitinib (Sutent) for patients with metastatic RCC. The trial led to the FDA approval of the combination as a frontline treatment for intermediate- and poor-risk patients with advanced RCC.  

In an analysis presented at the 2018 ESMO Congress, investigators evaluated the treatment-free interval (TFI) following discontinuation of first-line nivolumab plus ipilimumab or sunitinib in patients with advanced RCC on the CheckMate-214 trial. Findings from this analysis showed that in patients with intermediate- or poor-risk disease, nivolumab plus ipilimumab was associated with a significantly longer TFI. Investigators noted that TFI should be considered as a part of the traditional efficacy measures when evaluating therapeutic options for patients with advanced RCC.

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses an analysis of the CheckMate-214 study in advanced renal cell carcinoma (RCC).
 

Dr. McDermott on an Analysis of the CheckMate-214 Study in RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses novel immunotherapy combinations for patients with metastatic renal cell carcinoma (RCC).

According to McDermott, an exciting area of study is the combination of VEGF blockade and PD-1/PD-L1 blockade. There are 5 or 6 large randomized trials looking at various combinations, explains McDermott. The early data from phase I trials show that there are high response rates and longer progression-free survival (PFS) than expected with either strategy alone.

As we get into 2018 and 2019, we will start seeing the results of these randomized trials, says McDermott. If they are positive, there could be the fusion of the 2 effective strategies for kidney cancer in the first-line setting. Perhaps there will be 5 or 6 versions of combinations, which will be the next big thing for metastatic patients.

Several such combinations are under investigation, with the most data available so far being from a phase Ib study of axitinib (Inlyta) plus pembrolizumab (Keytruda). The results of this study were for 52 patients with advanced RCC who received frontline treatment with axitinib plus pembrolizumab. The overall response rate was 67.3% (35 patients), including 2 complete responses and 33 partial responses. The researchers also reported that the combination was well tolerated.

Dr. McDermott on Novel Immunotherapy Combinations in RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses immunotherapy as a standard of care for patients with renal cell carcinoma (RCC). 

According to McDermott, immunotherapy will be the standard of care for patients with RCC in 2018; however, it will not benefit everyone.  

Patients with good-risk clinical features did very well with sunitinib (Sutent) in the CheckMate-214 trial, so there may be some patients who could benefit from single-agent VEGF inhibitors, explains McDermott.  

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses immunotherapy as a standard of care for patients with renal cell carcinoma (RCC).

Dr. McDermott on Immunotherapy as a Standard of Care in RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses nivolumab (Opdivo) as a single agent for the treatment of patients with renal cell carcinoma (RCC).

Nivolumab is currently FDA approved for patients with RCC who have failed VEGF therapy in the second-line, but McDermott said that its therapeutic index and toxicity profile makes it a good candidate for first-line treatment.

In order to move this agent to the frontline, more work must be done to develop biomarkers to select patients who would benefit from single-agent nivolumab.

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses nivolumab (Opdivo) as a single-agent for the treatment of patients with renal cell carcinoma.

Dr. McDermott on Single-Agent Nivolumab in RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in renal cell carcinoma (RCC).

The CheckMate-214 study evaluated the combination of PD-1 blockade with nivolumab and CTLA4 blockade with ipilimumab.

This combination was particularly impactful in patients who were intermediate- and poor-risk, as they demonstrated a longer progression-free survival, a significantly longer overall survival (OS), and a higher complete response rate, McDermott explains.

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in renal cell carcinoma (RCC).
 

Dr. McDermott on Nivolumab Plus Ipilimumab in RCC

David F. McDermott, MD, director, Biologic Therapy and Cutaneous Oncology Programs, Hematology/Oncology, Beth Israel Deaconess Medical Center, discusses the role of VEGF-targeted therapy in renal cell carcinoma (RCC).

For most newly diagnosed patients, the standard of care is a

-targeted agent, as clear cell kidney cancers are very VEGF driven, McDermott says.

Many patients end up developing resistance though—at least half within the first year&mdash;suggesting the need for the development of new therapies in this setting.

David F. McDermott, MD, director, Biologic Therapy and Cutaneous Oncology Programs, Hematology/Oncology, Beth Israel Deaconess Medical Center, discusses the role of VEGF-targeted therapy in renal cell carcinoma. 

Dr. McDermott on the Role of VEGF Targeted Therapy in RCC

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses the immune-related toxicities for patients receiving checkpoint inhibitors for treatment of their renal cell carcinoma (RCC).

Adverse events (AEs) with all checkpoint inhibitors are fairly consistent with one another but greatly differ from chemotherapy and targeted agents, McDermott explains. Common related toxicities include inflammation in body organs where the T cells exist and attack healthy issue. Physicians must thoroughly educate their patients about these immune-related AEs and ensure that they report them so they can be appropriately managed. Many of the side effects, he adds, are reversible.

While grade 3/4 complications are relatively less common at approximately 20% of patients, there are some who can die from toxicities associated with immunotherapy if they are not caught and managed quickly. Additionally, he cautions, early intervention will not necessarily shut off the T-cell immune response.

David F. McDermott, MD, director of the Biologic Therapy Program at Beth Israel Deaconess Medical Center, discusses the immune-related toxicities for patients receiving checkpoint inhibitors for treatment of their renal cell carcinoma.