Evolution of Frontline VEGF TKI/Immunotherapy Treatments Propels Field of Renal Cell Carcinoma

Laura Wood, RN, MSN, OCN

VEGF tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) regimens have played a significant role in improving progression-free survival (PFS) and overall survival (OS) in patients with renal cell carcinoma (RCC), according to Laura Wood, RN, MSN, OCN.

“We’re seeing impressive improvements in long-term outcomes with the newer regimens in advanced renal cancer,” Wood, who is a retired oncology nurse specialist at Cleveland Clinic, said in an interview with Oncology Nursing News®. “TKI/IO combinations have made a huge impact on clinical outcomes and quality of life for patients with advanced RCC.”

Wood recently gave a talk on updates in renal cell and urothelial carcinomas as part of the 6th Annual School of Nursing Oncology™ meeting. Following the meeting, Wood met with Oncology Nursing News® to give a recap of the key takeaways in RCC for nurses.

Evolution of Treatments

In her presentation, Wood noted that the treatment of metastatic RCC has undergone multiple eras, starting with the use of cytokine-directed therapies, such as IL-2 and IFNα.

The targeted therapy era ushered in numerous treatments, including sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), bevacizumab (Avastin), everolimus (Afinitor), pazopanib (Votrient), axitinib (Inlyta), cabozantinib (Cabometyx), lenvatinib (Lenvima), and tivozanib (Fotdiva).

In 2015, the first immunotherapy entered the scene with the approval of nivolumab (Opdivo) and soon thereafter the combination of ipilimumab (Yervoy)/nivolumab was added to the landscape as well. In 2019, the first combination of immunotherapy plus VEGF/TKI was approved, marking a new and exciting area in the treatment of renal cell carcinoma.

Two such combinations were approved in 2019: pembrolizumab (Keytruda) and axitinib, and avelumab (Bavencio) and axitinib. In 2021, 2 more combinations were added to the fold: nivolumab/cabozantinib and pembrolizumab/lenvatinib.

Key Studies in Combination Therapies

According to Wood, there are 4 key studies which have drastically shifted VEGF/TKI combination regimens to the forefront of the treatment landscape. These include CheckMate 214 (NCT02231749), JAVELIN Renal 101 (NCT02684006), KEYNOTE-426 (NCT02853331), and CheckMate 9ER (NCT03141177).¹

CheckMate 214

The CheckMate 214 trial was a phase 3 trial which randomly assigned a total of 1096 patients to receive either nivolumab plus ipilimumab intravenously (IV) every 3 weeks for 4 doses followed by nivolumab for 2 weeks, or 50 mg of daily oral sunitinib (Sutent) for the first 4 weeks of a 6-week cycle. Nivolumab doses were 3 mg/kg and ipilimumab was 1 mg/kg.²

The median follow-up time was 25.2 months, at which time it was revealed that among intermediate- and poor-risk patients (n = 550), the 18-month OS rate was 75% (95% CI, 70%-78%) with dual immunotherapy and 60% (95%, 55%-66%) with sunitinib. Moreover, the median OS was not reached with nivolumab plus ipilimumab compared with 26.0 months with sunitinib (HR, 0.63; P < .001).²

Between the 2 groups, the objective response rate was 42% vs 27% (P < .001) and the complete response rate was 9% vs 1%; median PFS was 11.6 months and 8.4 months, respectively (HR, 0.82; P = .03).

Findings from the positive trial supported the FDA’s approval of the combination in 2018.

JAVELIN Renal 101

JAVELIN was a single-group, phase 1b trial which randomly assigned 886 patients 1:1 to receive either IV avelumab every 2 weeks plus 5 mg daily oral axitinib or 50 mg of daily oral sunitinib for the first 4 weeks of a 6-week cycle. The dose for avelumab was 10 mg/kg.³

In the combination arm (n = 442), the median PFS was 13.8 months vs 8.4 months in the single-agent arm (n = 444; HR, 0.69; 95% CI, 0.56-0.84; P < .001). In an analysis of patients with PD-L1 expressing tumors, the median PFS was 13.8 months vs 7.2 months, respectively (HR 0.61; 95% CI, 0.47-0.79; P < .001). In the same subpopulation, the overall response rate was 55.2% vs 25.5% with the combination and single-agents, respectively, and the median OS was 11.6 months vs 10.7 months.

Findings from the positive trial supported the FDA’s approval of the combination in 2019.

KEYNOTE-426

The phase 1b KEYNOTE-426 trial randomly assigned patients 861 to receive either combination therapy with IV pembrolizumab and oral axitinib (n = 432) or sunitinib (n = 429). Pembrolizumab was administered at a dose of 200 mg every 3 weeks and axitinib was taken twice daily at a dose of 5 mg. Sunitinib was taken at a dosage of 50 mg once daily for the first 4 weeks of a 6-week cycle.⁴

The median follow-up time was 12.8 months. At follow-up, the percentage of patients who had survived the first 12 months was 89.9% with pembrolizumab/axitinib vs 78.3% with sunitinib (HR 0.53, 95% CI, 0.38-0.74; P < .0001). The objective response rate between the 2 groups was 59.3% (95% CI, 54.5%-63.9%) and 35.7% (95% CI, 31.1%-40.4%).

Findings from the positive trial supported the FDA’s approval of the combination in 2019.

CheckMate 9ER

CheckMate 9ER was a phase 3, open-label trial which randomly assigned 651 adults to receive either nivolumab (240 mg every 2 weeks) and cabozantinib (40 mg once daily) or 50 mg of daily oral sunitinib 4 weeks of each 6-week cycle.⁵

At a median follow-up of 18.1 months, the median PFS was 16.6 months (95% CI, 12.5-24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0-9.7; HR, 0.51; 95% CI, 0.41-0.64; P < .001). The probability of surviving 12 months with the dual immunotherapy was 85.7% (95% CI, 81.3%-89.1%) and 75.6% (95% CI, 70.5%-80.0%; HR, 0.60; 98.89% CI, 0.40-0.89; P = .001) with the targeted therapy. The overall response rate between the 2 cohorts was 55.7% and 27.1%, respectively (P < .001).

Findings from the trial supported the FDA’s approval of the combination in 2021.

Nursing Considerations With Combination Treatment

The goal behind combination treatment is to combine the mechanism of actions of the drugs with single-agent efficacy—ideally using drugs with limited overlapping toxicities which can be given to a patient at their respective full dose.

When caring for patients with RCC, baseline symptom assessment is key, Wood noted. This includes reviewing the comorbidities, concomitant medications, and any adverse events (AEs) experienced with prior lines of therapy.

Patient and caregiver education should revolve around key indicators that should result in a phone call to the oncology care team.

Further, details regarding AEs, specific interventions, and assessing for improvement is key for nurses to consider, she added, particularly with the blossoming number of VEGF/immunotherapy combinations.

For example, AEs commonly associated with VEGF-targeted therapy include hypertension, taste changes, mucositis, dyspepsia, myelosuppression, and hand-foot syndrome.⁶ In contrast, common AEs of immunotherapy include pruritis, myocarditis, adrenal insufficiency, rash, pneumonitis, colitis, and hepatitis.⁶

However, it is important to note that certain AEs may overlap between the 2 treatment approaches. These include rash, fatigue, diarrhea, LFT elevations, hypothyroidism, anorexia, and altered mental status. If a patient is experiencing one of these symptoms, it is important to determine which drug is causing it to properly address it.⁶

Taking the drugs half-life into consideration is a good place to start, Wood said in her presentation, citing that the therapeutic half-life for axitinib, cabozantinib, lenvatinib, pazopanib, and sunitinib, are approximately 2.5 to 6 hours, 120 hours, 28 hours, 31 hours, and 40 to 60 hours, respectively. Moreover, some experts have suggested that in a patient being treated with axitinib plus pembrolizumab, for example, stopping the targeted treatment for a few days may be a way to rule out whether it is a targeted or immune-related toxicity, since an axitinib-induced toxicity would be expected to significantly improve with cessation of targeted therapy and an immune-related AE would not improve at all.⁶

“Nursing best practices include detailed education for patients and caregivers regarding early identification and intervention for possible immune-related AEs so oncology providers can minimize possible negative [effects] on treatment outcomes and provide the best opportunity for patients to have successful treatments,” Wood told Oncology Nursing News®.

The Future of RCC and Investigative Treatments At Play

As of August 2022, studies attempting to incorporate VEGF TKIs into the adjuvant setting have been unsuccessful⁷ and single-agent therapy is still the standard of care for treatment in the adjuvant setting, with sunitinib and pembrolizumab representing the 2 approved agents.

The EVEREST trial (NCT01120249) is an ongoing phase 3 trial assessing the safety and efficacy of everolimus in the adjuvant setting for patients with high-risk disease. At the 2022 ASCO Annual Meeting, the adjuvant use of the mTOR inhibitor was associated with a 21% reduction in the risk of recurrence or death compared with placebo for patients with very high-risk RCC, however, additional analyses of the study remain ongoing.⁷

Moreover, biomarkers have yet to play a role in treatment-decision making in the RCC space but Wood encourages nurses to be aware of biomarkers as certain patients may be eligible for clinical trials.

“[Although] biomarkers play a role in some treatments for urothelial cancer, there are no current biomarkers that impact treatment decisions in RCC,” Wood said. “[However,] clinical trials in both malignancies include tumor biopsies for biomarker testing, and it’s important that nurses understand this and encourage patients to be willing to have tumor biopsies done as requested so we can improve our ability to individualize treatment recommendations based on the person’s tumor biology,” she concluded.

References

1. Wood L. Novel approaches to Renal and Urothelial Cancers. Presented at: 6th Annual School of Nursing Oncology™; July 29-30, 2022; San Diego, CA.
2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126
3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi:10.1056/NEJMoa1816047
4. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714
5. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982
6. Wood LS, Ornstein MC. Toxicity management of front-Line pembrolizumab combined with axitinib in clear cell metastatic renal cell carcinoma: a case study approach. JCO Oncol Pract. 2020;16(suppl 2):15s-19s. doi:10.1200/JOP.19.00647
7. Ryan CW, Tangen C, Heath EI, et al. EVEREST: everolimus for renal cancer ensuing surgical therapy—a phase III study (SWOG S0931, NCT01120249). J Clin Oncol. 2022;40 (suppl 17):LBA4500. doi:10.1200/JCO.2022.40.17_suppl.LBA4500