KEYNOTE-564: Adjuvant immunotherapy for renal cell carcinoma.

SUMMARY

Renal cell carcinoma (RCC) accounts for 3% of all the cancers and has a 2% reported annual rise in the incidence over the past two decades.[1] Despite extensive research, no form of adjuvant therapy has shown a meaningful survival advantage or is practiced widely for this malignancy.

KEYNOTE-564 was an international, phase three, randomized, double-blind trial involving patients with clear cell RCC at high risk for recurrence post nephrectomy.[2] The protocol defined the high-risk criteria as T2 tumors with nuclear grade four or sarcomatoid morphology, T3-4 tumors, regional lymph node metastasis, metastatic disease post nephrectomy, and metastasectomy without evidence of disease.

Patients were randomly assigned to receive either adjuvant pembrolizumab or a placebo in a 1:1 ratio for a period of 1 year (maximum 17 cycles). The primary end-point was disease-free survival and was defined as the time to first local or distant recurrence or death from any cause. The critical secondary end-point was overall survival and efficacy was evaluated in the intention-to-treat population.

The trial randomized 994 patients either to adjuvant pembrolizumab (n = 496) or to placebo (n = 498) arms. At the time of reporting of this preplanned interim analysis, performed at a median period of 24 months post randomization, 260 events of recurrence or death had occurred (pembrolizumab (n = 109); placebo (n = 151)). Adjuvant pembrolizumab therapy was associated with significantly higher disease-free events (77% versus 68%) with a hazard ratio of 0.68 (95% confidence interval 0.53–0.87; P = 0.002) for recurrence or death. In the pembrolizumab arm, 61% of the patients received all the 17 planned treatment cycles and 21% discontinued the treatment due to adverse events and 10% discontinued as they developed recurrence. Grade three to five adverse events were reported in 32% and 18% of the patients who received pembrolizumab and placebo, respectively, and no treatment-related deaths were recorded.

The authors concluded that adjuvant pembrolizumab therapy significantly improved the disease-free survival as compared to a placebo in patients with RCC who were at high risk of recurrence post nephrectomy.

COMMENTS

Nephrectomy is the current standard of care for locally advanced RCC, although more than half of these patients develop recurrence, primarily as distant metastases, significantly compromising survival. Despite the proven benefit of targeted agents in patients with metastatic RCC, trials reported till date have failed to demonstrate a meaningful survival advantage for these agents when used in the adjuvant setting for non-metastatic disease.

A recent meta-analysis included four, phase-three, randomized controlled trials (ASSURE, S-TRAC, PROTECT, ATLAS) evaluating adjuvant tyrosine kinase inhibitors (TKIs) in patients with clear cell RCC[3] [Table 1]. The lack of overall survival benefit, poor tolerability resulting in dose reductions, and poor quality of life led the authors to conclude a lack of clinical benefit.

Table 1

Randomized controlled trials on adjuvant tyrosine kinase inhibitors in renal cell carcinoma

Trial	Inclusion criteria (histology, stage, grade)	Drug	n	DFS	OS	Dose reduction (%)	Gd 3/4 AE (%)
ASSURE	Clear/nonclear-cell high-risk RCC (pT1b (G3-4) N0 to Tany N+M0)	Sunitinib Sorafenib Placebo	647 649 647	48% at 5 years 50% at 5 years 50% at 5 years	75% at 5 years 80% at 5 years 76% at 5 years	At onset#	63 72 25
S-TRAC	Clear-cell locoregional RCC (≥PT3N0 or Tany N+M0)	Sunitinib Placebo	309 306	HR: 0.74 (95% CI: 0.55-0.99) P=0.04	HR: 0.92 (95% CI: 0.66-1.28) P=0.6	34	60 19
PROTECT	Clear-cell high-risk RCC (pT2(G3-4) N0 to Tany N+M0)	Pazopanib Placebo	571 564	HR: 0.86 (95% CI: 0.7-1.06) P=0.16	HR: 0.79 (95% CI: 0.57-1.09) P=0.16	51-60$	60 21
ATLAS	Clear-cell high-risk RCC (≥pT2 and/or N+M0, any grade)	Axitinib Placebo	363 361	HR: 0.87 (95% CI: 0.66-1.15) P=0.32	NR	56	61 30

# Due to the high rate of toxicity-related discontinuation, the starting dose of each drug was reduced, $Due to the high rate of toxicity-related attrition, the starting dose was reduced. After that, 60% dose-reduction was seen with 800mg initial dose and 51% with 600 mg. n=Number of participants, DFS=Disease-free survival, OS=Overall survival, Gd 3/4 AE=Grade 3 or 4 adverse events, HR=Hazard ratio, CI=Confidence interval, NR=Not reached

Recent reports demonstrating the survival benefit of immune checkpoint inhibitors (ICIs) in patients with metastatic RCC has revived interest in adjuvant therapy for RCC. Extrapolating from the benefit of pembrolizumab in metastatic RCC as seen in KEYNOTE-426 and CLEAR trials[45] [Table 2], the current trial evaluated pembrolizumab in an adjuvant setting. The improvement in the disease-free survival was primarily driven by reduced distant recurrences in the pembrolizumab group, and the overall incidence of distant recurrence, local recurrence, and all-cause death events was 20%, 5%, and 5%, respectively. The adverse effect profile was also superior to that reported with TKIs, with no need for dose reduction and only around 20% of the treatment discontinuation were attributed to adverse events. However, the reported survival benefit may actually be inflated as the study included higher-risk patients than those in the TKI trials, with 89% T3 tumors, 66% grade three or four, and the inclusion of metastatic cancers.

Table 2

Randomized controlled trials on pembrolizumab in metastatic renal cell carcinoma

Trial	Drug	Follow-up# (months)	n	PFS	OS
KEYNOTE 426	Pembrolizumab + axitinib versus Sunitinib	30	432 429	HR: 0.71 (95% CI: 0.60-0.84) P<0.0001	HR: 0.68 (95% CI: 0.55-0.85) P=0.0003
CLEAR	Pembrolizumab + lenvatinib versus Sunitinib	26	355 357	HR: 0.39 (95% CI: 0.32-0.49) P>0.001	HR: 0.66 (95% CI: 0.49-0.88) P=0.005

# Median follow-up in months. n=Number of participants, PFS=Progression-free survival, OS=Overall survival, HR=Hazard ratio, CI=Confidence interval

A growing matter of concern is the lack of a proper definition of high-risk group who are likely to benefit from the adjuvant therapy. In this study, patients with wide range of high risk factors were included, and the majority were positive for programmed death ligand-1 (PDL-1), aknown target for pembrolizumab. Long-term data, with subgroup analyses for individual risk factors, may help better define the patient sub-group with an appropriate risk-benefit profile. The benefit of adjuvant therapy in patients with nonclear-cell RCC also remains questionable.

Currently, pembrolizumab is approved only in combination with a TKI in patients with metastatic RCC, based on the KEYNOTE-426 and CLEAR trials,[45] and the optimum adjuvant regimen is yet to be defined. If the long-term follow-up data confirms an overall survival advantage, the dilemma of neoadjuvant versus adjuvant therapy and the optimum management of recurrences after adjuvant treatment will also need evaluation.

The study's primary limitation was the lack of long term follow-up, with only 26% of the deaths required for the overall survival evaluation. With the long-term outcomes awaited, the trial indicates that adjuvant therapy for high-risk RCC may be useful and the ongoing trials evaluating other ICIs including nivolumab (PROSPER; NCT03055013), atezolizumab (IMmotion010; NCT03024996), and durvalumab (RAMPART; NCT03288532), will further shed light on the matter.