CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: March 25, 2024
Expiration: March 24, 2025
KEYNOTE-564: Pembrolizumab as Adjuvant Therapy for Clear Cell RCC at Increased Risk of Recurrence
Rana R. McKay, MD:
We will now transition this discussion over to RCC. KEYNOTE-564 was a randomized, double-blind, phase III study of pembrolizumab as adjuvant therapy for patients with clear cell RCC having undergone nephrectomy, who were at increased risk of recurrence following resection.43 Patients were randomized to receive pembrolizumab, given for up to 1 year, vs placebo. The primary endpoint of this study was DFS per investigator assessment. Key secondary endpoints included OS and safety.
The primary endpoint of DFS was previously reported.44,45 At ASCO GU, the investigators presented updated data regarding long-term OS.
KEYNOTE-564: Baseline Characteristics
Rana R. McKay, MD:
The baseline characteristics between patients in the 2 arms were similar with regards to age, gender, ECOG PS, region of enrollment, and risk category from M0 intermediate high, M0 high or M1 NED.43
KEYNOTE-564: Overall Survival at Third Interim Analysis
Rana R. McKay, MD:
Investigators reported a significant improvement in OS at the third planned interim analysis in patients who received pembrolizumab compared with patients who received placebo.43 Median OS was not yet reached in both arms, but the HR of 0.62 was statistically significant (95% CI: 0.44-0.87, P = .002).
The landmark 2-year OS rate was 96.3% in the pembrolizumab arm vs 93.9% with the placebo arm. The 48-month OS rate was 91.2% with pembrolizumab vs 86.0% with placebo.
Of importance, this is the first checkpoint inhibitor immunotherapy that demonstrated improvement in OS in the adjuvant setting for any solid tumor malignancy. This really is a milestone, not just for RCC but also across other solid tumor malignancies. These data are absolutely practice changing and will certainly impact guidelines.
KEYNOTE-564: Overall Survival by Subgroups
Rana R. McKay, MD:
In terms of OS, there was a clear benefit of treatment with pembrolizumab across nearly all the subgroups that were evaluated by age, race, PS, region of enrollment, and disease risk status.43,44
KEYNOTE-564: Updated Disease-Free Survival
Rana R. McKay, MD:
This presentation also included updated data on DFS, which remained positive.43-45 The 48-month DFS rate was 64.9% among patients in the pembrolizumab arm, compared with 56.6% in the placebo arm (HR: 0.72, 95% CI: 0.59-0.87). It is encouraging to see consistent benefit in DFS with longer follow-up.
KEYNOTE-564: Updated DFS by Subgroups
Rana R. McKay, MD:
Consistent with the OS data, the DFS benefit was observed across key subgroups that were evaluated with a clear trend of the HR favoring pembrolizumab across all groups.43
KEYNOTE-564: Updated Safety in As-Treated Population
Rana R. McKay, MD:
With regards to the safety data for this regimen, no new safety signals were observed with pembrolizumab and the AEs were as expected.43 The rate of treatment-related grade 3/4 AEs associated with pembrolizumab was consistently 18.6% in both the prior analysis and updated analysis. There were no treatment-related deaths on this study.
KEYNOTE-564: Clinical Implications
Rana R. McKay, MD:
I think this is really a landmark study across all solid tumors. It is absolutely going to change treatment patterns for patients with localized RCC having undergone resection, who are at increased risk of recurrence, with the improvement in both DFS and OS.
The notion here is that we are not only delaying progression but hopefully also potentially preventing progression with the use of adjuvant pembrolizumab.
As we move forward, we are going to need to understand patient selection for therapy in the real world and better refine selection to avoid overtreatment and target individuals at greatest risk of recurrence who will respond to immunotherapy.
Terence Friedlander, MD:
I agree this is going to become the standard of care for patients with resected clear cell RCC. It is great to see that pembrolizumab can prolong survival when given in the adjuvant context.
CheckMate 914: Adjuvant Nivolumab for Localized RCC at High Risk of Relapse after Nephrectomy
Rana R. McKay, MD:
The next study I want to highlight is the phase III CheckMate 914 trial examining adjuvant nivolumab or adjuvant nivolumab plus ipilimumab compared with placebo for patients with clear cell RCC having undergone resection and with increased risk of disease recurrence.46 The primary endpoint of this study was DFS for nivolumab vs placebo.
Investigators previously presented data regarding the comparison of nivolumab plus ipilimumab to placebo.46 At this analysis, investigators report the outcomes for patients who received nivolumab vs patients who received placebo.
CheckMate 914: Nivolumab vs Placebo Disease-Free Survival per BICR, Primary Endpoint
Rana R. McKay, MD:
Unfortunately, this study did not meet its primary endpoint, which was DFS by independent review for nivolumab vs placebo.46 There was no significant difference in DFS between the 2 arms with the median DFS not yet reached and an HR of 0.87 (95% CI: 0.63-1.21, P = .3962).
CheckMate 914: Clinical Implications
Rana R. McKay, MD:
At the present time, adjuvant nivolumab is not a standard of care for patients with RCC post resection who have increased risk of recurrence.
There are many reasons that may explain why the results of this study are negative compared with KEYNOTE-564 discussed above, which demonstrated positive results. CheckMate 914 enrolled a lower-risk population and did not enroll patients with M1 NED. This study also enrolled patients who had T1 disease. In CheckMate 914, therapy was only administered over a 6-month period, as opposed to a 1-year period in KEYNOTE-564. So, although CheckMate 914 was negative, these results certainly do not take away from the positivity of KEYNOTE-564.
CheckMate 9ER 55 Month Follow-Up: Nivolumab Plus Cabozantinib vs Sunitinib for Untreated RCC
Rana R. McKay, MD:
Investigators also recently reported updated data from the phase III CheckMate 9ER study at 55 months of follow-up. CheckMate 9ER compared the combination of nivolumab plus cabozantinib vs sunitinib for patients with untreated advanced clear cell RCC.33,47,48 Patients were randomized to receive either nivolumab plus cabozantinib or sunitinib. The primary endpoint was PFS by BICR. Key secondary endpoints were OS, ORR, and safety.
CheckMate 9ER 55 Month Follow-Up: Efficacy in the ITT Population
Rana R. McKay, MD:
With regards to the updated efficacy results in the ITT population, investigators continue to observe a consistent benefit with nivolumab plus cabozantinib in PFS, OS, and ORR.33,47,48
The median PFS with nivolumab plus cabozantinib was significantly better at 16.4 months vs 8.4 months with sunitinib (HR: 0.58, 95% CI: 0.49-0.70).48 In terms of OS, the HR continued to hold steady at 0.77 (95% CI: 0.63-0.95). The ORR with the combination was 55.7%, with a complete response rate of 13.6%. Altogether, these results have certainly improved from prior analyses.
CheckMate 9ER 55 Month Follow-Up: Efficacy in the IMDC Favorable-Risk Population
Rana R. McKay, MD:
In the favorable-risk patient population, investigators continue to observe a PFS benefit in patients treated with nivolumab plus cabozantinib (HR:0.69, 95% CI: 0.48-1.00).33,47,48
However, it is hard to discern an OS benefit with nivolumab plus cabozantinib vs sunitinib in the favorable-risk patient subgroup. The median OS was 52.9 months with nivolumab plus cabozantinib vs 58.9 months with sunitinib (HR: 1.1, 95% CI: 0.69-1.75).
I think is possible that investigators did not observe an OS benefit here because favorable-risk patients tend to do well in general. They tend to see multiple sequential lines of treatment. These factors may make it more challenging to discern differences in treatment efficacy in this population.
In the favorable-risk population, the ORR with nivolumab plus cabozantinib improved at 66.2% vs 44.4% with sunitinib treatment.
CheckMate 9ER 55 Month Follow-Up: Efficacy in the IMDC Intermediate/Poor-Risk Population
Rana R. McKay, MD:
In addition, the intermediate- and poor-risk patients demonstrate the most dramatic activity of nivolumab plus cabozantinib, with across the board improvements in PFS, OS, and response rates associated with this combination therapy.48
CheckMate 9ER 55 Month Follow-Up: Clinical Implications
Rana R. McKay, MD:
The long-term follow-up of this study continues to highlight that nivolumab plus cabozantinib is a very active regimen with improvements across all efficacy parameters, including PFS, OS, and response rate, particularly for those patients with intermediate- and poor-risk disease.48 I think the long-term data presented here is really important to understand the benefit of this regimen with regards to OS.
CheckMate 214 Long-Term Follow-Up: Nivolumab and Ipilimumab vs Sunitinib for Advanced RCC
Rana R. McKay, MD:
Continuing the trend of updates on long-term follow-up data, I would like to discuss updated data from the phase III CheckMate 214 trial. This was a frontline study enrolling patients with advanced clear cell RCC who had not received any prior therapy.49 Patients were randomized to either nivolumab plus ipilimumab or sunitinib. In this study, the primary endpoints were OS, PFS, and ORR in the International Metastatic RCC Database Consortium (IMDC) intermediate- and poor-risk population.
The data presented here are with a 99.1-month median follow-up, which is really striking, encompassing 8 years of follow-up data from this study.49
CheckMate 214 Long-Term Follow-Up: Overall Survival
Rana R. McKay, MD:
In the ITT population, investigators continue to see a dramatic OS benefit of nivolumab plus ipilimumab compared with sunitinib with a HR of 0.72 (95% CI: 0.62-0.83).49-51
In the intermediate- to poor-risk patients, nivolumab plus ipilimumab exhibited a pronounced improvement in OS vs sunitinib, with a HR of 0.69 (95% CI: 0.59-0.81). The median OS with nivolumab plus ipilimumab was 46.7 months compared with 26 months with sunitinib.
Of importance, as investigators followed the favorable-risk patients over time, the difference in OS between nivolumab plus ipilimumab and sunitinib grew more pronounced with an HR of 0.82 (95% CI: 0.60-1.13). Initially, there did not seem to be a difference in OS between the 2 treatment arms in this patient population. However, long-term follow-up revealed the OS benefit associated with nivolumab plus ipilimumab.
CheckMate 214 Long-Term Follow-Up: Progression-Free Survival
Rana R. McKay, MD:
In the ITT population, there was a flattening of the PFS curve around 24 months.49 At this point, the PFS differences between the 2 treatment arms were beginning to become apparent. Now, investigators report the 90-month landmark PFS rate by independent review of 22.8% for nivolumab plus ipilimumab vs 10.8% for sunitinib (HR: 0.88, 95% CI: 0.75-1.03).
In terms of PFS in different risk subgroups, in the intermediate- and poor-risk population the HR is 0.73 (95% CI: 0.61-0.87).49 In contrast, the favorable-risk population did not exhibit any difference in PFS between the 2 treatment arms, with an HR of 1.76 (95% CI: 1.25-2.48). Initially, it even appeared that PFS was worse among favorable-risk patients treated with of nivolumab plus ipilimumab, but that difference leveled out over time.
CheckMate 214 Long-Term Follow-Up: Duration of Response, ORR, and Best Overall Response
Rana R. McKay, MD:
With regards to duration of response, it is striking that among intermediate- and poor-risk patients, the median duration of response is 82.8 months with nivolumab plus ipilimumab vs 19.8 months with sunitinib (HR: 0.48, 95% CI: 0.33-0.69).49 In the favorable-risk population, median duration of response was 61.5 months in the nivolumab plus ipilimumab group, compared with 33.2 months in the sunitinib group (HR: 0.70, 95% CI: 0.36-1.34).
I think this 8-year follow-up data truly emphasizes the long-term durability of the response elicited by nivolumab plus ipilimumab across all risk groups.
CheckMate 214 Long-Term Follow-Up: Clinical Implications
Rana R. McKay, MD:
This study clearly has many clinical implications. I think it has implications for how HCPs think about immunotherapy combinations, particularly for favorable-risk patients. These data clearly demonstrate the long-term benefit of nivolumab plus ipilimumab and suggest that some patients could potentially be cured with this regimen. I do think that these data are going to impact future guidelines on therapy selection for favorable-risk patients and continue to reinforce using this regimen for patients with intermediate- and poor-risk disease.
CheckMate 67T: Subcutaneous Nivolumab vs Intravenous Nivolumab
Rana R. McKay, MD:
I also want to highlight data from the phase III CheckMate 67T trial. This was a novel study that assessed a new, subcutaneous form of nivolumab with recombinant human hyaluronidase vs standard IV nivolumab, with the goal of providing options for patients and streamlining efficiency within the clinic.52
This study enrolled patients with advanced or metastatic clear cell RCC who progressed during or after 1 to 2 prior lines of therapy and had not received prior immunotherapy. Patients were randomized to receive subcutaneous nivolumab every 4 weeks vs IV nivolumab every 2 weeks. The coprimary pharmacokinetic endpoints of this study were noninferiority of the average serum concentration of drug at Day 28 and the trough serum concentration at steady state. A key secondary endpoint was noninferiority of ORR by BICR.
CheckMate 67T: Coprimary Pharmacokinetic Endpoints and ORR by BICR
Rana R. McKay, MD:
Both the coprimary endpoints of pharmacokinetic noninferiority were met with subcutaneous nivolumab.52 The geometric mean ratio of the average serum concentration of drug at Day 28 of subcutaneous vs IV nivolumab was 2.098, while the geometric mean ratio of the trough serum concentration at steady state of subcutaneous vs IV nivolumab was 1.774. Clearly, these data demonstrate noninferiority between the regimens.
In addition, the ORR was 60% with the subcutaneous formulation compared with 45% with the IV formulation.52 Thus, noninferiority was also demonstrated for the key secondary endpoint.
CheckMate 67T: Safety
Rana R. McKay, MD:
The rates of AEs, treatment-related AEs, serious AEs, and AEs leading to discontinuation for subcutaneous nivolumab were similar or lower than IV nivolumab.52
With regards to study drug toxicity, there were 3 deaths in the subcutaneous nivolumab arm compared with 1 in the IV nivolumab arm. Local site reactions were the main AE associated with subcutaneous nivolumab. These reactions were low-grade, transient, tended to last a median duration of about 3 days, and most resolved without treatment. There were no anaphylactic reactions that were observed on either treatment arm.
CheckMate 67T: Clinical Implications
Rana R. McKay, MD:
This study clearly has implications supporting subcutaneous delivery of nivolumab and with regard to our healthcare delivery efforts. This is encouraging, since subcutaneous administration of medications can be a lot simpler than IV administration. Hopefully, incorporating subcutaneous administration of nivolumab can provide opportunities to improve healthcare efficiency, the patient experience through the clinic, and to mitigate chair time in the infusion centers.
Terence Friedlander, MD:
I agree, broadly that this can be a new treatment option for patients. We will have to see whether the skin reactions limit the use of the therapy in some patients, but overall it has the potential to shorten the time spent in infusion centers, which is a net benefit for patients and the health system.
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