Targeting Cancer With Tyrosine Kinase Inhibition in Frontline HCC

Comparing IO/IO and IO/TKI Frontline Regimens in Clear Cell RCC

During a live virtual event, Thomas Hutson, MD, PharmD, discussed the 4 frontline combination regimens including immunotherapies and tyrosine kinase inhibitors. This is the first of 2 articles based on this live event.


  • A 59-year-old Black woman received a diagnosis of clear cell renal cell carcinoma (RCC)​.
  • She underwent left radical nephrectomy in December 2019​.
  • Nine months later, she developed metastatic disease to both lungs, mediastinum (35 x 38 mm), and retroperitoneal lymph nodes​.
  • Diagnosis: stage IV RCC, clear-cell histology, with metastases to lungs and retroperitoneum​
  • Karnofsky performance status: 90%​
  • Hemoglobin: 11.1 g/dL​
  • Corrected calcium, neutrophils, platelets: within normal limits​

Targeted OncologyTM: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for a patient like this?

THOMAS HUTSON, DO, PHARMD: The NCCN guidelines show the preferred regimens that are recommended for favorable and poor/intermediate risk; giving category 1 to a regimen means uniform consensus in the NCCN panel members. All of the IO/TKI [immuno-oncology/tyrosine kinase inhibitor] combinations are listed as preferred for favorable risk.1 You don’t see single-agent therapy listed as preferred for favorable risk. They’re listed as “other recommended regimens”.

The clinical trial data show although there may be slightly more toxicity, that there’s a greater progression-free survival [PFS] and response rate with an IO/TKI approach. On the other hand, you can make an argument survival is not impacted much, but some of the other efficacy end points are; enough that the panel recommended doing combination therapy for all patients that you elect to treat.1

With that said, it’s probably not unreasonable to have a small percentage of patients that you treat with single agent, in select situations, and it’s not unreasonable to have some patients that you watch and wait. For the poor/intermediate group, which is going to represent roughly 80% of the patients you’re going to see walking in the door…the IO/TKI and IO/IO approaches are given category 1. Then, for patients who are not candidates for IO therapy for whatever reason, there’s single-agent cabozantinib [Cabometyx] listed, but it’s not given a category 1 recommendation.

The NCCN guidelines are fairly broad, but they allow you to feel comfortable using an IO/TKI combination. You don’t need to do an IMDC [International Metastatic RCC Database Consortium] risk calculation to choose that; you [can] feel pretty comfortable that you’ll have benefit across the board with an IO/TKI. By checking to see if the patient meets poor risk features using the risk model, or just clinically by how they’re presenting—you can usually tell a poor-risk individual by their symptoms [and so forth]. Then, that may open up the door for an IO/IO approach.

What are the IO-containing regimens that are recommended for frontline therapy, and how do they compare in outcomes for patients?

There is ipilimumab/nivolumab [Yervoy/Opdivo], and then the other IO/TKIs, axitinib [Inlyta] plus pembrolizumab [Keytruda] being the earliest approved IO/TKI, and hence has roughly 48 months or so follow-up.2,3 [Cabozantinib/nivolumab has the next-most follow-up.4] And, the regimen that was most recently approved was the lenvatinib [Lenvima] plus pembrolizumab.5 The regimen that had the longest follow-up is the IO/IO, and that is the [ipilimumab/nivolumab regimen from] CheckMate 214 [NCT02231749] with over 5 years follow-up.6

There is a split of the favorable-, intermediate-, and poor-risk participants. Not all of these trials had the same population of patients. And, although in general they enrolled patients with clear cell histology, there were enough differences in the patient enrollment that we can’t do fair cross-trial comparisons, although [we will compare them]. But some of these changes in the percentage of patients in [each of] the IMDC risk groups could be enough to sway results. For instance, if you have a trial that seems to have more of the patients with favorable-risk status, you know you’re going to have results that are going to be skewed for longer survival, versus [a trial with] a larger number of patients with poor-risk status.

The hazard ratio for survival is a good way to look across trials. The hazard ratios for overall survival [OS] are very similar; they’re within standard errors of each other.6-9 The only thing you can spring out is that you have the longest follow-up with ipilimumab/nivolumab, so that hazard ratio of 0.72 has stood the test of time, if you will.6 The PFS, although positive with ipilimumab/nivolumab when compared with sunitinib [Sutent] in the CheckMate 214 trial, has the least favorable hazard ratio with it. That shouldn’t be surprising. There was a time when we weren’t sure that you could see PFS benefits with an IO approach. Its claim to fame is not on its PFS benefit, it’s on the duration with OS. With the IO/TKIs, they have better PFS hazard ratios, and then with the CLEAR study [NCT02811861] of the lenvatinib/pembrolizumab regimen has the greatest benefit on paper of any of the IO/TKIs, and it boasts a hazard ratio of 0.39.9

When it comes to objective tumor response rate [ORR], it is something similar; the IO/IO seems to work in fewer patients.2 It does beat sunitinib in ORR, but as a much smaller margin. And again, lenvatinib/pembrolizumab has a pretty profound benefit, almost a doubling in benefit, in ORR.5

The CR [complete response] rate of most of the agents is within a standard error, roughly 10% to 12%; the outlier being the CLEAR study with a 16% CR.2-5 The progressive disease [PD] rate is an outlier [for ipilimumab/nivolumab in] CheckMate 214—it seems to work in fewer patients based on its [lower] ORR [versus the IO/TKI combinations]. So, there is an absolute PD rate of roughly 20% as best response.2 If you look the trial data, there’s another group of about 10% of patients who could not be assessed. So I would lump that in together [with PD], and I say 20% to 30% of patients don’t have benefit with an IO/IO, in regard to seeing the tumor shrink [or have stable disease (SD)]. They have PD as their best response, and they go on to receive other therapies, while with the IO/TKI combinations work in almost every patient.3-5

When we get down to the level of cabozantinib/nivolumab and lenvatinib/pembrolizumab, 95% of patients are having at least SD.4,5 So, that’s very comforting; no one wants to tell the patient they have progression after the first scan.

There is more efficacy when it comes to tumor shrinkage and PFS with the IO/TKI combination. It’s lacking the concept of durability that the IO/IO regimen has, because we now have 5-year follow-up with the IO/IO regimen.6 The question we have in the field is: Will the IO/TKI combinations show the same type of benefit in the 30% of patients that seem to have a flatline on their survival curve at 5 years? Will there be this group of patients with whom you can stop therapy, and can they be maintained off therapy? That’s the big question we can’t answer yet.


1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2023. Accessed July 25, 2022.

2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

4. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

5. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

6. Motzer RJ, Tannir NM, McDermott DF, et al. 661P - Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol. 2021;32(suppl_5):S678-S724. doi:10.1016/annonc/annonc675

7. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): Results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500

8. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(6_suppl):350-350. doi:10.1200/JCO.2022.40.6_suppl.350

9. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab versus sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Presented at: Kidney Cancer Research Summit 2021. October 7-8, 2021. Philadelphia, PA. Accessed July 25, 2022.