TKI and PD-L1 Therapy Combinations Show Long-Term Durability in Advanced RCC


In this Q&A discussion, Hans Hammers, MD, PhD, explains the rationale for continued use of tyrosine kinase inhibitor and PD-L1 therapy combinations, like lenvatinib and pembrolizumab, for patients with advanced renal cell carcinoma.


A 59-year-old Black woman with a left renal mass​ underwent left radical nephrectomy, which revealed clear cell renal cell carcinoma (ccRCC)​.

Nine months later​:

The patient developed nodules in both lungs, with mediastinal (35 × 38 mm) and retroperitoneal lymph nodes​.

Diagnostic workup​:

  • Lung biopsy confirmed stage IV RCC, clear cell histology​
  • Karnofsky performance status: 90%​
  • Hemoglobin: 11.1 g/dL​
  • Corrected calcium, neutrophils, platelets: Within normal limits​


The patient began pembrolizumab (Keytruda) at 200 mg given every 3 weeks, plus 20 mg of lenvatinib (Lenvima) given once daily. At 8 weeks, a follow-up CT scan showed partial response​ to treatment. Ten weeks after treatment initiation​, the patient contacted the office reporting an at-home blood pressure of 160/110 mmHg​.

  • The following day, in-office blood pressure was 170/115 mmHg​.
  • Antihypertensive therapy was initiated.
  • Pembrolizumab plus lenvatinib was continued​.
  • Hypertension persisted despite up-titration of antihypertensive every 2 weeks.
  • Lenvatinib was held and blood pressure stabilized around 130-140 / 80-90 mmHg on antihypertensive​.
  • Lenvatinib resumed at 14 mg once a day.

Targeted Oncology: What did the data from the CheckMate 214 trial (NCT02231749) show for the use of immunotherapy combination therapy in this patient population?

Hans Hammers, MD, PhD​

UT Southwestern Medical Center​

Dallas, TX

Hans Hammers, MD, PhD​

UT Southwestern Medical Center​

Dallas, TX

HANS HAMMERS, MD, PhD​: This is the original pivotal trial...that [gave us a new first-line therapy] when it we pitted it against sunitinib [Sutent].... The power of this study was divided between 3 co-primary end points, which was the overall response rate [ORR], overall survival [OS], and progression-free survival [PFS].1 For some of these end points they needed to have a low P value, because the P value was split [among these end points], but nonetheless, [the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) showed] a slight benefit...roughly at 60 [weeks of treatment]. We can speculate there might have been some patients in this window who might have done better with an earlier tyrosine kinase inhibitor [TKI].1

For example, when you see a nicer version [of data like this], you want to see the distance between [how soon and strong patients respond to therapy] maintained, which tends to happen more with PD-L1 and TKI combinations.... With this kind of immunotherapy treatment, the wildcard is the PFS, which in this study plateaued at 31% of patients [at a median of 67.7 months of follow-up compared with 11% of patients on sunitinib at this time].

What data led to the approval of lenvatinib and pembrolizumab for a patient case like this?

[The CLEAR study] led to the approval of the lenvatinib and pembrolizumab combination starting at 20 mg,2 which is higher than what we're used to from the nivolumab and ipilimumab combination vs sunitinib. The primary end point was PFS, and the secondary end point was OS, and with a median follow up of 33.7 months. This created an impressive curve [between the study arms].3 There is a nice separation [of results between the arms at a median of 23.3 months with lenvatinib compared with 9.2 months without] with a low HR of 0.42 [95% CI, 0.34-0.52].... This separation of the Kaplan-Meier curves occurs at the 2-year mark, it's a very potent combination still.

What other efficacy data from the CLEAR study would you highlight?

Initially, there was a high complete response rate of 17.2% [for patients on lenvatinib and pembrolizumab], and a high ORR of 71.0% with a progressive disease [PD] rate of just 5.4%.3 The high ORR was probably because this agent is very viable [in this patient population] despite some of the toxicity issues we have previously seen with this approach. In the 4-year follow-up, the median OS was 53.7 months, which is very respectable, but is similar between the OS on sunitinib at 54.3 months.4 There is still a difference with PFS with the combination compared with sunitinib [at a median of 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0), respectively (HR 0.47; 95% CI, 0.38-0.57, P < .0001)], which speaks to the fact that we have good second-line therapies.4

What was the safety data with this combination?

Looking at the treatment exposure, safety, and discontinuation data, there is a high rate of grade 3 adverse events [AEs] at 82.4% with lenvatinib.5 I think anytime you combine anything with a TKI you can get grade 3 toxicities in the range of 70% or more, so this is not unexpected. Also not unexpected was the rate of patients with dose reductions on lenvatinib was approximately 70%. I do have some patients who are still on 20 mg [of lenvatinib] with dose interruptions, but I'd say most patients eventually need to go down to 14 mg [of lenvatinib].5


1. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180

2. Motzer RJ, Russo P, Gruenwald V, et al. Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: results from the randomized, phase 3 CheckMate 914 trial. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089

3. Porta CG, Eto M, Motzer RJ, et al. Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study. Ann Oncol. 2022;33(suppl_7):S660-S680. doi:10.1016/annonc/annonc1072

4. Motzer RJ, Porta CG, Eto M, et al. Final prespecified overall survival (OS) analysis of CLEAR: 4-year follow-up of lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2023;41(16):4502. doi:10.1200/JCO.2023.41.16_suppl.4502

5. Motzer RJ, Alkeseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021; 384:1289-1300. doi:10.1056/NEJMoa2035716

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