Neoadjuvant and adjuvant therapies have become an area of growing interest for treating patients with renal cell carcinoma (RCC) because of the potential to improve outcomes for patients with locally advanced disease.

This approach has shown promise with checkpoint inhibitors, and adjuvant pembrolizumab (Keytruda) was recently approved for the treatment of patients with RCC at intermediate or high risk of recurrence following nephrectomy.

 Further research is looking to brining this approach to therapy—not just with immunotherapy but also with targeted therapy—into practice ahead
of nephrectomy to further prevent the risk of recurrence.

One such trial is the global phase 3 PROSPER RCC trial (NCT03055013) looking at neoadjuvant and adjuvant nivolumab (Opdivo) in patients with high-risk RCC scheduled for radical or partial nephrectomy. Naomi B. Haas, MD, is the medical oncology study monitor for the trial and expects this will have a significant impact on the future role of neoadjuvant and adjuvant immunotherapy for patients with RCC.

 during the 2021 International Kidney Cancer Symposium, Haas, the director of the Prostate and Kidney Cancer Program and professor of medicine at the Hospital of the University of Pennsylvania, discussed the potential of the neoadjuvant approach in treating patients with RCC as well as ongoing research in this setting.

Targeted OncologyTM: Can you discuss what has been the success of the neoadjuvant targeted/immunotherapy strategy in the treatment of patients with RCC?

: A number of VEGF TKI [tyrosine kinase inhibitor] approaches have been taken in the neoadjuvant setting. The general approach has been, given that cabozantinib [Cabometyx] is one of the VEGF TKIs, that it is thought to be one of the most active in RCC. [With this approach], the idea has been if it can be administered in a safe way and achieve as much tumor shrinkage as possible. One of the challenges with VEGFR TKIs, in general in the neoadjuvant setting, has been that they interfere with wound healing to some extent. Cabozantinib has a half-life of about 5 days, so the timing of it has to be such that it can be administered, and then I allow enough time to stop [treatment] where the patient can safely proceed with surgery but also not be off the drug so much that a rebound effect [occurs]. And I think we’ve seen with other trials that that is indeed possible.


The neoadjuvant approach has been an important approach for the immune checkpoint inhibitors. People [previously] have made comments without any data, only based on personal experience [about immune checkpoint inhibitors’ efficacy]. Several years ago, somebody stood up at a meeting and made the comment that there might be more scarring seen with immune checkpoint inhibitor therapy before surgery, and that makes surgery difficult. There have been a couple of neoadjuvant phase 2 trials that have been conducted that have shown that it is a safe approach and it hasn’t made surgery impossible in these patients, because immune checkpoint inhibitor therapy doesn’t interfere with wound healing, and I think the concerns about things like pneumonitis and intubating a patient have not borne out, that increasingly people are feeling a little bit better about offering that as a neoadjuvant approach.

What were the important points made by the panelists during the session regarding neoadjuvant therapy?


One of the very valuable things that neoadjuvant therapy does is it allows people to understand the biology of the tumors and who is benefiting and who isn’t benefiting from these approaches by doing some of the valuable correlative and molecular work that is needed. I think that one of the other take-home messages is that there’s still a relative lack of consensus, so we do need to wait for some of the bigger trials. For example, the PROSPER trial is trying to address both the feasibility, the safety, and also the signal that is achieved by offering neoadjuvant therapy to patients. I think one of the other [important] messages is that we need to figure out how to address these kinds of trials so they’re available to everybody and not just at tertiary cancer centers.

What are the key challenges with designing neoadjuvant trials in this disease?


One of them is good coordination between the urology and the medical oncology teams. Usually, the urologist is the first person to see the patients. So urologists have to be aware of neoadjuvant approaches and have to be willing to have that conversation with patients ahead of time to alert them to clinical trials. It’s not the standard of care right now to offer neoadjuvant [treatment] for RCC, but certainly, there’s a lot of surgical experience in urothelial malignancies and also in other disease sites, such as colorectal cancer and breast cancer, where it is common. One of the impediments is the urologist bringing it up to the patients. The second is being able to coordinate care because generally these drugs are administered by a medical oncologist. So [it is the] speed in getting patients [to treatment that is key] and having a multidisciplinary approach. The other [challenge] is making a trial simple enough for the medical oncologist, the urologist, and the patient to all feel that it’s easily accomplished and easy to enroll.

What are your expectations for neoadjuvant trial design going forward?


I think it’s not going to go away. I think that neoadjuvant therapy trials can also help to understand, in addition to who benefits from any kind of perioperative treatment, whether it’s adjuvant or neoadjuvant based on the correlatives, but I also think that people are getting more comfortable with this approach. It was a real learning experience several years ago when the PROSPER trial launched, but I think a lot of urologists now have a comfort level that they didn’t have before. I think that one of the other values is understanding the duration of either the neoadjuvant or the adjuvant approaches.

Since then, lenvatinib (Lenvima) has become such an important drug in the RCC space, and there are ongoing trials in the neoadjuvant setting and for other diseases like thyroid cancer and hepatocellular carcinoma. Do you think we’re close to having a study of neoadjuvant lenvatinib in RCC?

We’re about to launch a lenvatinib plus pembrolizumab trial at the University of Pennsylvania. I also heard Dr [Viraj] Master also talk about [a trial] at Emory [University] [NCT04393350]. There are phase 2 initiatives that are being done to understand the benefit in patients. Lenvatinib is an interesting drug because it probably has some immunologic aspects that can augment its activity with immune checkpoint inhibitors. There [are] some data to suggest that it might help stimulate Tregs [regulatory T cells] and it might be a way to prevent T-cell exhaustion, which are 2 reasons that immune checkpoint inhibitors sometimes don’t work in patients. I think it’s a very useful approach, and so I feel encouraged about that.

FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed December 9, 2021. https://bit.ly/3rNXC3R

Articles

Neoadjuvant Therapy Is a Significant Focus of Ongoing Research for RCC

In the open-label phase 2 trial (NCT03635892), cabozantinib (Cabometyx) plus nivolumab (Opdivo) showed promising efficacy in metastatic non–clear cell renal cell carcinoma (nccRCC) among patients with papillary, unclassified, or translocation-associated histologies, according to findings presented in a poster at the 2021 International Kidney Cancer Symposium.

Although kidney cancer encompasses many different subtypes of cancer based on pathobiology that vary in sensitivity to treatments, clear cell renal cell carcinoma (ccRCC) makes up 60% to 80% of kidney cancer cases and is found to be dependent on VEGF signaling.

 The rest are considered to be nccRCC, which comprises a heterogeneous mix of malignancies.

Previously, the combination of cabozantinib and nivolumab showed improved efficacy over sunitinib (Sutent) in patients with advanced ccRCC in the phase 3 CheckMate 9ER trial (NCT03141177).

The phase 2 study enrolled patients with advanced or metastatic nccRCC who did not receive prior PD-1/PD-L1– targeted treatment. The study was split into 2 cohorts. Cohort 1 included patients with papillary, unclassified, or translocation-associated RCC. Cohort 2 included patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST v1.1, and the secondary end points were progression-free survival (PFS), overall survival (OS), and safety.

A total of 47 patients between the 2 cohorts were treated with 40 mg of oral cabozantinib daily plus 240 mg of nivolumab intravenously every 2 weeks or 480 mg intravenously every 4 weeks.

Patients must have had advanced or metastatic nccRCC, 0 or 1 prior lines of systemic therapy, and measurable disease according to RECIST v1.1 to be included in the trial. Cohort 1 initially consisted of 20 patients and functioned within its single-stage design, met its primary end point, and was later expanded to 40 patients to find a more precise estimate for ORR. Cohort 2 consisted of 7 patients and had a Simon 2-stage design that closed early.

The median age of patients was 57 years (range, 33-78) and 54 years (range, 46-68) in cohorts 1 and 2, respectively. Overall, 66% of patients were male and 72% had a Karnofsky performance score of 90, with the remainder having a score of 80. In cohort 1, 80% had papillary histology, 15% were unclassified without papillary features, and 5% had translocation-associated disease.

The majority of patients had intermediate-risk disease by both risk stratification systems and had undergone prior nephrectomy. Patients had a median of 2 sites of disease (range, 1-7).

Between the 2 cohorts, 31 (66%) patients received no prior treatment, 16 (34%) received 1 prior line of systemic treatment, 12 (26%) received prior VEGF-targeted therapy, 8 (17%) received prior mTOR-targeted therapy, and 2 (4%) patients received chemotherapy.

Patients were followed for a median of 13.1 months (range, 2.2-28.6).

The ORR was 48% (95% CI, 31.5%-63.9%) for patients in cohort 1, and no responses were reported in cohort 2. Within cohort 1, 15 of 32 patients with papillary histology showed an objective response (47%; 95% CI, 29%-65%). A response was seen in 3 of 6 patients with unclassified RCC, and 1 of 2 patients with translocation-associated RCC also responded to the combination regimen. All responses were partial responses (PRs). Half of all patients in cohort 1 and 71% in cohort 2 achieved stable disease (SD).

The disease control rate was 98% (95% CI, 86.8%-99.9%) in cohort 1 and 71% (95% CI, 29.0%- 96.3%) in cohort 2. Clinical benefit (PR or SD ≥ 24 weeks) was achieved in 58% (95% CI, 40.9%-73.0%) of patients in cohort 1 and 29% (95% CI, 3.7%-71.0%) in cohort 2.

Cohort 1 had a median PFS of 12.5 months (95% CI, 6.3-16.4) and a median OS of 28.0 months (95% CI, 16.3–not evaluable [NE]). At 12 months, the PFS rate was 52.8% and the 18-month OS rate was 68.7%.

Five of 6 patients with NF2 mutations and 4 of 5 patients with FH mutations had an objective response. Of the 6 patients with SETD2 mutations, only 1 showed a response to treatment. These genomic studies emphasize the diversity within nccRCC and will require further investigation to determine their role as predictors of response to systemic therapy, they study's authors, led by Chung-Han Lee MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, New York, wrote in the poster.

The median treatment duration was 11.0 months (95% CI, 7.8-21.1) between the 2 cohorts.

Treatment-related adverse events (TRAEs) of any grade were reported in 87% of patients and grade 3/4 events in 32%. TRAEs led to discontinuation of either agent in 21% of patients and discontinuation of both agents in 9%.

The most common TRAEs of any grade were fatigue (57%), palmar-plantar erythrodysesthesia syndrome (57%), diarrhea (53%), hypertension (38%), and dry mouth (36%).

This safety profile was similar to that of the CheckMate 9ER trial studying the cabozantinib and nivolumab combination in patients with ccRCC, the study authors noted in the poster.

1. Lee CH, Voss MG, Carlo MI, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: results of a phase 2 trial. Presented at: Interna- tional Kidney Cancer Symposium 2021; November 5-6, 2021; Austin, TX, and virtual. Abstract E43.

2. Linehan WM. Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics. Genome Res. 2012;22(11):2089-2100. doi:10.1101/ gr.131110.111
3. 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

Cabozantinib/Nivolumab Combination Demonstrates Efficacy in nccRCC

With an extra 7 months’ median follow-up of patients in the phase 3 CLEAR trial (NCT02811861), efficacy with the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) was maintained in patients with advanced renal cell carcinoma (RCC), according to updated findings presented at the 2021 International Kidney Cancer Symposium.1 Although neither the lenvatinib/pembrolizumab arm nor the sunitinib (Sutent) treatment arm reached a median overall survival (OS) in all randomized patients, a trend for improvement was seen with the combination regimen.

“No substantial changes in efficacy end points were observed from the original data cutoff date,” study authors, led by Toni K. Chouieri, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, wrote in their poster. “Along with the previously observed efficacy benefits with lenvatinib plus pembrolizumab, this follow-up analysis further supports lenvatinib plus pembrolizumab as a first-line treatment for patients with advanced RCC.”

The CLEAR study explored frontline treatment for patients with advanced RCC with a clear cell component. Enrolled patients had a Karnofsky performance status of at least 70 and adequate organ function. These patients were randomized 1:1:1 to receive either lenvatinib 20 mg daily plus pembrolizumab 200 mg intravenously every 3 weeks, lenvatinib 18 mg daily plus everolimus (Afinitor) 5 mg daily, or sunitinib monotherapy 50 mg daily for 4 weeks on and 2 weeks off treatment. The primary end point was progression-free survival (PFS) by independent review committee. Prior cutoff for the initial results of the trial was on August 28, 2020, with a median follow-up of 26.6 months.

This study led to the FDA approval of lenvatinib and pembrolizumab for the first-line treatment of adult patients with advanced RCC.

 This arm and the standard-of-care comparator arm of sunitinib monotherapy were the focus of the updated analysis, which comprised a median follow-up of 33.7 months for lenvatinib and pembrolizumab with a cutoff date of March 31, 2021.

Of the 355 patients in the lenvatinib/pembrolizumab arm, the median age was 64 (range, 34-88), 63.9% had intermediate risk by Memorial Sloan Kettering Cancer Center (MSKCC) criteria, 59.2% had intermediate risk by International Metastatic RCC Database Consortium criteria (IMDC), 7.9% had sarcomatoid features, 30.1% had positive PD-L1 expression, and 73.8% had undergone prior nephrectomy. In the sunitinib arm (n = 357), the median age was 61 years (range, 29-82), 63.9% had intermediate risk by MSKCC criteria, 53.8% had intermediate risk by IMDC criteria, 5.9% had sarcomatoid features, 33.3% had positive PD-L1 expression, and 77.0% had undergone prior nephrectomy. As of the updated cutoff date, 32.1% of patients in the lenvatinib/pembrolizumab arm and 13.7% in the sunitinib arm were receiving ongoing treatment.

The median PFS was 22.1 months (95% CI, 18.2-27.7) with lenvatinib and pembrolizumab treatment compared with 9.5 months (95% CI, 7.9-11.1) with sunitinib treatment (HR, 0.47; 95% CI, 0.38-0.57). The study authors noted that PFS was assessed in the analysis only by investigators by RECIST criteria.

Median OS was not estimable in both treatment arms (HR, 0.72; 95% CI, 0.55-0.93). However, the Kaplan-Meier curves did eventually cross.

In a subgroup analysis for OS, patients with intermediate or poor risk showed an even greater benefit from lenvatinib/ pembrolizumab over sunitinib treatment compared with those with favorable risk; this was seen with both sets of prognostic risk criteria (TABLE1). However, Choueiri et al did note that the interpretation was limited by the low number of events.

The objective response rate was 68.7% (95% CI, 63.9%- 73.6%) in patients treated with lenvatinib and pembrolizumab compared with 34.5% (95% CI, 29.5%-39.4%) with sunitinib (relative risk, 2.00; 95% CI, 1.70-2.34). In the doublet arm, complete responses (CRs) were seen in 10.4%, partial responses (PRs) in 58.3%, and stable disease (SD) in 20.8%. The median time to response (TTR) was 1.94 months (range, 1.41-20.14) and the median duration of response (DOR) was 27.9 months (95% CI, 22.1-36.8).

In the sunitinib monotherapy arm, CRs were reported in 2.0%, PRs in 32.5%, and SD in 44.3%. The median TTR was 2.00 months (range, 1.51-17.28) and the median DOR was 14.8 months (95% CI, 11.6-17.3).

1. 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 (CLEAR study). Presented at: 2021 International Kidney Cancer Symposium; November 5-6, 2021; Austin, TX. Abstract E41.

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


3. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed December 9, 2021. https://bit.ly/3rZowFY

Extended CLEAR Trial Follow- Up Shows Maintained Efficacy of Lenvatinib/Sunitinib in RCC

 The frontline combination of nivolumab and cabozantinib may have survival benefit for patients with renal cell carcinoma.

Exploratory subgroup analyses from the phase 3 CheckMate 9ER trial (NCT03141177) suggested that the frontline combination of nivolumab (Opdivo) and cabozantinib (Cabometyx) showed improvement in survival in patients with advanced renal cell carcinoma (RCC) and bone metastasis over sunitinib (Sutent).

Although both progression-free survival (PFS) and overall survival (OS) were improved with nivolumab/cabozantinib over sunitinib in patients without bone metastasis, the improvement was even greater in those with bone metastasis, according to results of a post hoc analysis presented in a poster during the 2021 International Kidney Cancer Symposium.

The overall safety profile of the combination was comparable in patients with and without bone metastasis and was consistent with that of all randomized patients in the trial, the study authors, led by Andrea B. Apolo, MD, of the National Cancer Institute, wrote in their poster. They added that there was a higher incidence of grade 3/4 adverse events (AEs) with nivolumab/cabozantinib over sunitinib in patients with bone metastasis.

The CheckMate 9ER trial enrolled 651 patients with advanced or metastatic RCC who were previously untreated and had clear cell histology. Seventy-nine patients treated with nivolumab/cabozantinib had bone metastasis at baseline.

These patients had a slightly higher median age compared with those treated with sunitinib (63 vs 61, respectively) and lower Karnofsky performance status compared with those without bone metastasis. More patients with bone metastasis had received radiotherapy compared with those without bone metastasis. Several patients with bone metastasis received prior or concomitant bone-targeted therapies to treat their metastasis, including denosumab and bisphosphonates.

In patients with bone metastasis, the median PFS among those treated with nivolumab/cabozantinib was 18.2 months (95% CI, 8.3-20.1) vs 4.4 months (95% CI, 3.7-7.0) with sunitinib monotherapy (HR, 0.38; 95% CI, 0.25-0.59). In those without bone metastasis, the median PFS was 17.0 months (95% CI, 12.5-20.0) with the combination and 9.5 months (95% CI, 7.9-11.0) with sunitinib (HR, 0.57; 95% CI, 0.45-0.72).

The median PFS among those treated with nivolumab/ cabozantinib was similar in those with or without bone metastasis (HR, 1.26; 95% CI, 0.90-1.76). With sunitinib, the median PFS was shorter in those with bone metastasis at baseline vs those without (HR, 1.85; 95% CI, 1.33-2.56).

Median OS among those with bone metastasis was not evaluable (NE) with nivolumab/cabozantinib (95% CI, 21.4- NE) compared with 29.5 months (95% CI, 12.5-NE) with sunitinib monotherapy (HR, 0.64; 95% CI, 0.39-1.06). The median OS was NE in both treatment arms among patients without bone metastasis (HR, 0.65; 95% CI, 0.46-0.91).

Median OS was shorter with combination therapy in those with bone metastasis at baseline compared with those without bone metastasis (HR, 1.72; 95% CI, 1.10-2.69). With sunitinib, the median OS was shorter in those with bone metastasis than in those without (HR, 1.69; 95% CI, 1.13-2.52).

Objective response rate (ORR) was higher among patients treated with nivolumab/cabozantinib with or without baseline bone metastasis. The ORR was 48% (95% CI, 37%-60%) in the nivolumab/cabozantinib arm among those with bone metastasis, which consisted of complete responses (CRs) in 6% and partial responses (PRs) in 42%; 34% had stable disease (SD). The median duration of response (DOR) was 18 months.

With sunitinib treatment in patients with baseline bone metastasis, the ORR was 11% (95% CI, 5%-21%), consisting of all PRs, and 40% had SD. The median DOR was 7 months.

Among those without bone metastasis, the ORR in the nivolumab/cabozantinib arm was 57% (95% CI, 51%-63%) and 33% (95% CI, 28%-39%) in the sunitinib arm. The median DOR was 22 months (95% CI, 17-NE) with nivolumab/cabozantinib and 13 months (95% CI, 10-21) with sunitinib.

Patients with bone metastasis treated with nivolumab/ cabozantinib had a higher degree of grade 3/4 treatment-related AEs than those treated with sunitinib (71% vs 42%, respectively) and those without bone metastasis treated with either regimen (59% vs 55%). In patients with bone metastasis treated with nivolumab/cabozantinib, the most common treatment-related AEs were lipase increase (11%), hyponatremia (10%), hypertension (9%), hypophosphatemia (8%), and asthenia (6%).

There were also more immune-mediated AEs with nivolumab/ cabozantinib treatment among patients with bone metastasis. The most common immune-mediated event of any grade was hypothyroidism in 29% of patients with bone metastasis and in 26% of those without bone metastasis.

Apolo A, Powles T, Bourlon MT, et al. Nivolumab plus cabozantinib vs sunitinib in patients with advanced renal cell carcinoma and bone metastasis: subgroup analysis of the phase 3 CheckMate 9ER trial. Presented at: 2021 International Kidney Cancer Symposium; November 5-6, 2021; Austin, TX. Abstract N22.

Clinical Articles

Nivolumab/Cabozantinib Improves Survival in Advanced RCC, Even With Bone Metastasis

An analysis from the phase 3 CLEAR trial (NCT02811861) of patients with advanced renal cell carcinoma (RCC) treated with the lenvatinib (Lenvima) plus pembrolizumab (Keytruda) regimen showed adverse reactions (ARs) most often occurred within the first 5 months of treatment.

The study authors, led by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, suggested in a poster presented at the 2021 International Kidney Cancer Symposium that proactive management of treatment-emergent adverse events (AEs), including treatment interruption, was crucial for patients receiving the regimen.

“Clinicians play a critical role in the prompt identification and management of ARs in patients with [advanced] RCC treated with lenvatinib plus pembrolizumab,” Motzer et al wrote in their poster. “Prompt management of ARs may potentially reduce treatment interruption(s) and/or lenvatinib dose reduction and allow patients to continue receiving therapy.”

In the analysis, AEs were defined by 12 different AR groupings: fatigue, diarrhea, musculoskeletal pain, hypothyroidism, hypertension, stomatitis, decreased appetite, rash, nausea, dysphonia, proteinuria, and weight decrease.

Of the 352 patients treated with at least 1 dose of the combination in the original CLEAR trial,

the total exposure was 542.9 person-years. The most common ARs of any grade reported were fatigue in 63.1%, diarrhea in 61.9%, musculoskeletal pain in 58.0%, hypothyroidism in 56.8%, hypertension in 56.3%, stomatitis in 43.2%, and decreased appetite in 40.6%. The most common grade 3 or higher ARs were hypertension in 28.7%, diarrhea in 9.9%, fatigue in 9.4%, weight decrease in 8.0%, and proteinuria in 7.7%.

The exposure-adjusted incidence of the most common ARs was 567 (1.08/total exposure) for diarrhea, 480 (0.91/ total exposure) for musculoskeletal pain, 370 (0.70/total exposure) for fatigue, and 340 (0.65/total exposure) for hypertension.

No difference was noted overall in the safety profile between patients who were 65 years or older and those who were under 65 years old.

The median time to first onset of all ARs was approximately 5 months.

The median time to first onset of hypertension of any grade was 3.0 weeks, with a minimum time of 0.1 weeks and a maximum time of 126.9 weeks. A total of 9.1% interrupted their lenvatinib dose due to hypertension, 11.9% reduced their dose of lenvatinib, and 0.9% discontinued lenvatinib. Pembrolizumab was interrupted in 3.1% and discontinued in 0.3%. With dysphonia, the median time to onset was 3.0 weeks, with a minimum of 0.1 weeks and a maximum of 129.3. Only 0.6% interrupted or reduced their dose of lenvatinib. Among patients experiencing fatigue, the median time to onset was 4.4 weeks, with a minimum of 0.1 weeks and a maximum of 128.3 weeks. Lenvatinib was interrupted in 11.1%, reduced in 9.7%, and discontinued in 0.6%. Pembrolizumab was interrupted in 7.4% and discontinued in 0.3%.

On the other end of the spectrum, the median time to onset of diarrhea was 20.0 weeks, with a minimum of 0.3 weeks and a maximum of 118.0 weeks. Lenvatinib was interrupted in 17.6%, reduced in 16.2%, and discontinued in 1.4%. Pembrolizumab was interrupted in 10.2% and discontinued in 1.1%. The minimum time to onset of weight decrease was 1.1 weeks, the maximum was 114.1 weeks, and the median was 17.4 weeks. Lenvatinib was interrupted in 2.6%, reduced in 2.8%, and discontinued in 0.3%.Pembrolizumab was interrupted in 1.4% and discontinued in 0.6%.

The median time to first onset of grade 3 or higher hypertension was 3.1 weeks, with a minimum of 0.1 weeks and a maximum of 126.9 weeks. Proteinuria of grade 3 or higher had a median of 5.1 weeks to onset, with a minimum of 2.0 weeks and a maximum of 108.1 weeks. Rash of grade 3 or higher had a median of 8.1 weeks to onset, with a minimum of 2.4 weeks and a maximum of 113.9 weeks. The median time to first onset of grade 3 or higher hypothyroidism was 9.1 weeks, with a minimum of 5.9 weeks and a maximum of 60.1 weeks.

On the other end of the spectrum, grade 3 or higher nausea had a median time to first onset of 62.0 weeks, with a minimum of 14.4 weeks and a maximum of 91.1 weeks. The median time to first onset of weight decrease was 51.0 weeks, with a minimum of 15.1 weeks and a maximum of 98.9 weeks.

For management of ARs in patients treated with the regimen, Motzer et al suggested baseline monitoring of blood pressure, urine protein levels, and thyroid and liver function. In the study, AEs were managed with dose modifications of lenvatinib, with reductions reported in 69% of patients. Lenvatinib was discontinued in 26% of patients, and pembrolizumab in 29%. Both were discontinued in 13%. The median time to first dose reduction of lenvatinib was 1.87 months (range, 0.10-37.98) and 4.14 months (range, 0.07-30.59) to first interruption.

According to the lenvatinib prescribing information, in the case of a persistent or intolerable grade 2 or 3 AR, it is recommended to withhold the drug until the AR improves to grade 1 or less, then resume therapy at a reduced dose.3 Permanent discontinuation is recommended in the case of a grade 4 AR. The original trial also recommended an antidiarrheal agent at the time of treatment initiation or the onset of symptoms.

From the standard 20-mg start dose of lenvatinib, given once daily, the first recommended reduction is to a 14-mg dose, followed by 10 mg, then 8 mg.

In the case of hypertension, blood pressure should be monitored after 1 week of treatment, then every 2 weeks for the first 2 months, followed by monthly thereafter, the study authors recommended.1 Lenvatinib should be withheld and later reduced in the case of grade 3 hypertension that does not alleviate with antihypertensive therapy. In the original study, if a patient was not already on an antihypertensive therapy, starting one would be indicated.

High-grade corticosteroids were taken by 14.8% of the patients in the original trial to manage immune-mediated AEs. If a grade 4 immune-mediated AE occurs, prescribing information recommends pembrolizumab be discontinued.

Understanding which agent is the causative agent for the AR helps to determine which agent to reduce or withhold. If there is no improvement, an immune-mediated AE may be considered, the study authors suggest.

1. Motzer R, Geore S, Merchan JR, et al. Characterization and management of adverse reactions in patients with advanced renal cell carcinoma receiving lenvatinib + pembrolizumab (CLEAR study). Presented at: 2021 International Kidney Cancer Symposium; November 5-6, 2021; Austin, TX. Abstract CTR14.

2. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

3. Lenvima. Prescribing information. Eisai Inc; 2021. https://bit.ly/3m0SzcW

4. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2021. https://bit. ly/3rYb0Tj

Proactive management of treatment-emergent adverse events, including treatment interruption, may be crucial for patients with renal cell carcinoma receiving lenvatinib in combination with pembrolizumab, according to the CLEAR study investigators.

Managing Adverse Reactions in Patients With RCC Treated With Lenvatinib/Pembrolizumab

Great progress has been made using immunotherapy in the frontline setting for the treatment of patients with metastatic renal cell carcinoma (RCC), including in 2021; however, most patients still die of the disease and more options and new targets are needed, according to a presentation by Moshe C. Ornstein, MD, MA, during the 2021 International Kidney Cancer Symposium.

In 1998, the median overall survival (OS) with interferon α-2a was 13 months, 12 months with interleukin-2, and 17 months with a combination of the agents.2 Since then, numerous combination trials have also yielded significant improvements in survival in the first-line setting (

). For instance, in 2018, the median OS with immunotherapy agents nivolumab (Opdivo) plus ipilimumab (Yervoy) was 55.7 months compared with 38.4 months with sunitinib (Sutent; HR, 0.72; 95% CI, 0.62-0.85; 

CheckMate 214 (NCT02231749), which evaluated nivolumab and ipilimumab vs sunitinib found both the combination and sunitinib monotherapy had a median progression-free survival (PFS) of 12.3 months (HR, 0.86; 95% CI, 0.73-1.01). The landmark 12-month OS rate was 83% with the combination vs 78% with the monotherapy. At 24 months, the landmark OS rate was 71% and 61%, respectively. The overall response rate (ORR) was 39% in the combination arm vs 32% in the monotherapy arm, with a complete response (CR) rate of 12% and 3% respectively.

The KEYNOTE-426 trial (NCT02853331) found that the combination of pembrolizumab (Keytruda) and axitinib (Inlyta), a tyrosine kinase inhibitor (TKI), had an OS of 45.7 months compared with 40.1 months with sunitinib monotherapy (HR, 0.73; 95% CI, 0.60- 0.88; 

< .001). The land-mark OS rate at 12 months was 90% with the combination and 79% with the monotherapy. At 24 months, the landmark OS rate was 74% and 66%, respectively. With the combination, the median PFS was 15.7 months compared with 11.1 months with the monotherapy (HR, 0.68; 95% CI, 0.58-0.80; 

< .0001). The ORR was 60.4% with the combination and 39.6% with sunitinib monotherapy, and the CR rate was 10% and 4%, respectively.

The CheckMate 9ER study (NCT03141177) looked at PD-1 inhibitor nivolumab plus cabozantinib (Cabometyx), a TKI, vs sunitinib. The median OS was not reached with the combination vs 29.5 months with the monotherapy (HR, 0.66; 95% CI, 0.50-0.87; 

= .0034). The 12-month OS rate was 86% for the combination and 76% for the monotherapy with the 24-month OS rate being 72% and 60%, respectively. The median PFS was 17.0 months with the combination vs 8.3 months with sunitinib alone (HR, 0.52; 95% CI, 0.43-0.64; 

< .0001). The ORR was 55% with the combination and 27% with the monotherapy, with a CR rate of 9% and 4%, respectively.7 The FDA approved the combination regimen as first-line treatment of patients with advanced RCC in January 2021.

The CLEAR trial (NCT02811861) evaluated the efficacy of pembrolizumab and the multitargeted TKI lenvatinib (Lenvima) vs pembrolizumab plus everolimus (Afinitor) vs sunitinib monotherapy. Although the median OS was not reached with either pembrolizumab/lenvatinib or sunitinib (HR, 0.66; 95% CI, 0.49-0.88; 

= .005), the 12-month OS rate for the lenvatinib combination was 90% vs an estimated rate of 79% for monotherapy, and the 24-month OS rate was 79% and 70%, respectively. The median PFS was 23.9 months with the combination and 9.2 months with the monotherapy (HR, 0.39; 95% CI, 0.32-0.49; 

< .001). The ORR was 71% in the combination arm and 36% with the monotherapy, with a CR rate of 16% and 4%, respectively.9 The FDA approved the combination of pembrolizumab and lenvatinib for the first-line treatment of adult patients with advanced RCC in August 2021.

“Although immunotherapy is great now, there is still a way to go,” said Ornstein, a genitourinary medical oncologist at the Cleveland Clinic Taussig Cancer Center. According to Ornstein, even with the higher and durable response rates seen with these frontline immunotherapy regimens, most patients still progress and die of metastatic RCC.

There are treatment options that have yet to be explored, according to Ornstein. These include using the metabolic pathway to improve immunotherapy response rates and cellular therapy. Additionally, the inhibition of anti-inflammatory cytokines is an option to help improve outcomes in the metastatic RCC population. “Understanding the local environment, the peripheral environment, in a static environment is how we develop the next wave of immunotherapy agents,” said Ornstein.

1. Ornstein M. Novel immunotherapy targets. Presented at: 2021 International Kidney Cancer Symposium; November 4-5, 2021; Austin, TX.

2. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleu-kin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d’Immunothérapie. 

1998;338(18):1272-1278. doi:10.1056/NEJM199804303381805

3. Powles T, Albiges L, Bex A, et al; ESMO Guidelines Committee. Renal cell carcinoma treatment recommendations. ESMO. September 28, 2021. Accessed November 5, 2021. https://bit.ly/3woKId8

4. Motzer RJ, Tannir NN, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 

2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

5. Rini BI, Plimack ER, Stus V, et al; KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. 

2019;380(12):1116-1127. doi:10.1056/NEJMoa1816714

6. 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. 

. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500

7. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. 

. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308

8. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. FDA. January 22, 2021. Accessed November 22, 2021. https://bit.ly/3FZiid2

9. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

10. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed November 22, 2021. https://bit.ly/3FZdy7q

Despite advanced in the field of renal cell carcinoma, most patients still die of the disease and more options and new targets are needed, says Moshe C. Ornstein, MD, MA.

Frontline Immunotherapy-Based Regimens Shift Survival Outcomes for Patients With Metastatic RCC

Long-term data from the phase 3 CheckMate 214 trial were presented by Nizar Tannir, MD, FACP, during the recent 2021 International Kidney Cancer Symposium.

First-line nivolumab (Opdivo) plus ipilimumab (Yervoy) produced a long-term survival of 5 years in some patients with advanced renal cell carcinoma (RCC), according to a poster on long-term data from the phase 3 CheckMate 214 trial (NCT02231749) presented by Nizar Tannir, MD, FACP, at the 2021 International Kidney Cancer Symposium.

 The combination replaced sunitinib (Sutent) as the standard of care for advanced RCC after the combination demonstrated superior long-term survival benefits in the trial.

During CheckMate 214, patients with previously untreated, advanced clear cell RCC were randomized 1:1 to receive either the experimental combination or the monotherapy. Patients were stratified by geographic region and International Metastatic RCC Database Consortium (IMDC) risk status. End points included overall survival, progression-free survival, and objective response rate (ORR).

In the experimental cohort’s intention-to-treat population (ITT; n = 550), the median age was 62 (range, 26-85) and 75% of patients were male. Prognostic scores were favorable for 23% of patients, intermediate for 61%, and poor for 17%. There were 11% of patients who had received prior radiotherapy and 82% who had undergone prior nephrectomy. Moreover, 78% of patients had 2 or more target or nontarget lesions with the median sum of reference diameters for target lesions being 65.5 mm (range, 10-357). Sites of metastasis included the lung (69%), lymph node (45%), bone (20%), and liver (18%). Less than 1% of quantifiable tumor PD-L1 expression was seen in 77% of patients.

In the ITT sunitinib group (n = 546), the median age was 62 (range, 38-81) and 73% were male. IMDC scores were favorable in 23% of patients, intermediate in 61%, and poor in 16%. Prior radiotherapy was seen in 13% of patients, with prior nephrectomy in 80% of patients. Additionally, 78% of patients had 2 or more target or nontarget lesions with the median sum of reference diameter being 63 mm (range, 10-359). Sites of metastases included the lung (68%), lymph node (49%), bone (22%), and liver (20%). Quantifiable tumor PD-L1 expression of 1% or less was observed in 75% of patients.

In the patients with long-term survival who were treated with the experimental combination (n = 236), the median age was 61 (range, 34-81) and 73% were male. IMDC scores were favorable in 29% of patients, intermediate in 61%, and poor in 11%. Prior radiotherapy was seen in 8% of patients and prior nephrectomy in 85% of patients. Additionally, 70% of patients had 2 or more target or nontarget lesions with the median sum of reference diameter being 50.5 mm (range, 10-276). Sites of metastasis included lung (69%), lymph node (41%), bone (11%), and liver (13%). Quantifiable tumor PD-L1 expression of 1% or more was seen in 24% of patients.

In patients treated with sunitinib who achieved long-term survival (n = 171), the median age was 61 (range, 32-85), with 74% being male. IMDC scores were favorable in 31% of patients, intermediate in 63%, and poor in 5%. Prior radiotherapy was reported in 9% of patients and prior nephrectomy in 91%. Additionally, 69% of patients had 2 or more target or nontarget lesions with the median sum of reference diameter being 48 mm (range, 10-283). Sites of metastases included lung (62%), lymph node (45%), bone (11%), and liver (16%). Quantifiable tumor PD-L1 expression of 1% or more was seen in 22% of patients.

At the 5-year follow-up, 14% of patients in the combination arm and 5% of patients in the monotherapy arm remained on treatment. Baseline characteristics of patients with long-term survival did not set them apart from the general patients, with the exception that these patients had lower target lesion burden at baseline and a smaller proportion of them had 2 or more target lesions.

In patients who had intermediate or poor IMDC scores who achieved long-term survival, 39% of patients in the combination arm required further systemic therapy compared with 75% of patients in the monotherapy arm. For patients who had a favorable-risk score, further systemic therapy was needed for 68% of patients in the experimental arm and 83% of patients in the sunitinib arm. In the overall long-term survival population, 48% of patients in the nivolumab/ipilimumab arm required subsequent systemic therapy compared with 78% of patients in the sunitinib arm.

The confirmed ORR of patients treated with the combination was 61% (95% CI, 55%-68%). A complete response (CR) was seen in 24% of patients and a partial response (PR) in 38%. Stable disease (SD) was seen in 33% of patients and progressive disease (PD) in 5% of patients. The median time to response (TTR) was 2.8 months and 77% were experiencing an ongoing response. Any tumor size reduction was seen in 86% of patients, with 61% of patients experiencing a reduction of 50% or more.

The confirmed ORR of patients in the sunitinib arm was 56% (95% CI, 48%-63%), with a CR rate of 9% and a PR of 47%. SD was seen in 32% of patients and PD in 9%. The median TTR was 4.0 months and 59% were experiencing an ongoing response. Additionally, 92% of patients saw a reduction in tumor size with 42% seeing a reduction of 50% or more.

In patients with intermediate-risk or poor-risk scores, the ORR was 71% (95% CI, 63%-77%) in the experimental cohort and 50% (95% CI, 40%-60%) in the monotherapy cohort. Additionally, 25% of patients in the nivolumab/ipilimumab arm had a CR compared with 6% of patients in the sunitinib arm. PRs were 46% and 44%, respectively. SD was seen in 25% of patients and PD was seen in 4% of patients in the combination arm. In the monotherapy arm, the SD rate was 34% and the PD rate was 13%. In the combination arm, the median TTR was 2.8 months compared with 4 months in the monotherapy arm. In the nivolumab/ipilimumab arm, an ongoing response was seen in 80% of patients compared with 55% of patients in the sunitinib arm. A reduction in tumor size of 50% or more was seen in 71% of patients in the combination arm and 37% of patients in the monotherapy arm. Any tumor reduction was seen in 87% of patients in the combination arm and 89% of patients in the monotherapy arm.

In patients with a favorable-risk score, the confirmed ORR of the combination arm was 41% (95% CI, 30%-53%) compared with 66% (95% CI, 53%-78%) in the monotherapy arm. A CR was seen in 22% of patients in the experimental arm and 14% in the sunitinib arm. PRs were seen in 19% and 53% of patients, respectively. SD was observed in 52% of patients in the combination arm and 27% in the monotherapy arm, with PD in 7% of patients in the experimental arm and 3% in the control arm. The median TTR was 2.8 months with nivolumab/ipilimumab and 4.2 months with sunitinib. An ongoing response was observed in 67% and 64% of patients, respectively. In the experimental arm, any reduction in tumor size was seen in 82% of patients, with a reduction of 50% or more in 40% of patients. In the control arm, any reduction was seen in 98% of patients, with 52% experiencing a reduction of 50% or more.

Across all patients with long-term survival and in all risk groups, the median duration of response was not reached with nivolumab and ipilimumab treatment vs 38.7 months (95% CI, 26.3-60.4) with sunitinib for all patients, 23.5 months (95% CI, 18.2-60.4) in those with intermediate-risk or poor-risk RCC, and 51.4 months (95% CI, 33.2–not evaluable) in those with favorable-risk disease.

More long-term responders in the nivolumab/ipilimumab arm experienced a treatment disruption than with sunitinib. A total of 54% of patients with intermediate- or poor-risk scores experienced a disruption in the experimental arm compared with 14% of patients in the control arm. In patients with a favorable score, disruptions were seen in 43% and 19% of patients, respectively. The median treatment-free interval was 42 months (range, 4-68) with the combination and 43 months (range, 16-60) with sunitinib in patients with intermediate/ poor risk. For patients with a favorable-risk score, the median disruption was 59 months (range, 7-68) with the combination vs 47 months (range, 4-62) with sunitinib.

Patients with long-term survival received an average of 41 doses (range, 1-154) of nivolumab and 4 doses (range, 1-4) of ipilimumab. Patients in the overall study population received an average of 14 doses (range, 1-154) of nivolumab and 4 doses (range, 1-4) of ipilimumab. Additionally, 79% of patients in the overall population and 88% of patients in the long-term survival cohort received 4 doses of ipilimumab.

Any-grade adverse events (AEs) seen in the long-term survival population treated with nivolumab plus ipilimumab included skin (61%), endocrine (39%), gastrointestinal (36%), hepatic (22%), renal (12%), and pulmonary (10%). Also, 11% of patients in this cohort experienced a grade 3/4 hepatic AE.

In patients treated with sunitinib, any-grade AEs included skin (74%), endocrine (39%), gastrointestinal (64%), hepatic (18%), renal (9%), and pulmonary (1%). Also, 15% of patients experienced a grade 3/4 skin-related AE.

In the overall study population, a treatment-related AE led to a discontinuation of 23% of patients in the combination arm vs 13% of patients in the monotherapy arm. For patients with long-term survival, a treatment-related AE led to discontinuation in 28% and 16% of patients, respectively.


1. Tannir N, Motzer R, McDermott D, et al. First-line nivolumab plus ipilimumab versus sunitinib in patients with long-term survival of ≥ 5 years in the CheckMate 214 trial. Presented at: 2021 International Kidney Cancer Symposium: North America; November 5-6, 2021; Austin, TX. Abstract CTR11.

2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. 