Lisa Astor is the Associate Editorial Director for Targeted Oncology. Astor received her Bachelor of Arts in English Literature from New York University.

Lisa Astor

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

Articles

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.

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

The treatment landscape for renal cell carcinoma (RCC) has expanded significantly over the past decade in the frontline setting with several new combinations becoming available for patients with clear cell histology. Most recently was the FDA approval of the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) based on the findings of the phase 3 CLEAR trial (NCT02811861).

Since the approval of the multikinase inhibitor lenvatinib in RCC, the agent is being investigated in various large trials to determine if further combinations can expand upon the benefit seen in the CLEAR trial. Some of these trials in progress were mentioned during the 2021 International Kidney Cancer Symposium, including the phase 3 MK-6482- 012 trial (NCT04736706) of the HIF-2α inhibitor belzutifan (Welireg) with lenvatinib vs pembrolizumab and quavonlimab a CTLA-4 inhibitor, vs pembrolizumab and lenvatinib in patients with advanced clear cell RCC with no prior treatment. MK-6482-011 (NCT04586231) is another phase 3 trial looking at the use of belzutifan plus lenvatinib vs cabozantinib (Cabometyx) in patients with RCC.

In an interview with Targeted Oncology™, Nicholas J. Vogelzang, MD, the chairman of medical oncology at Comprehensive Cancer Centers and a clinical professor of medicine at University of Nevada, Reno School of Medicine and University of Nevada, Las Vegas School of Medicine, discussed how the treatment landscape has changed for RCC and the continuing promise of lenvatinib.

Targeted Oncology™: Can you discuss some of the approvals that we’ve had and impressions of the different regimens? 

The landscape is confusing to everyone, including treating doctors. The longest approval has been nivolumab [Opdivo]/ipilimumab [Yervoy]. Those data with Dr Motzer have been available for about 5 years, so we’ve gotten used to using nivolumab/ipilimumab. That was approved for poor- or intermediate-risk disease and had the best benefit in patients with sarcomatoid histology. It left good-risk patients more or less out of the picture. Then we got approval for pembrolizumab and axitinib [Inlyta], and a lot of doctors liked pembrolizumab/axitinib because it covered good-risk [patients] and we had both a phase 2 and a phase 3 [trial as evidence]. A lot of doctors got comfortable with pembrolizumab and axitinib. Then we had, if you will, the not very positive study of avelumab and axitinib and that did not reach a survival end point compared with sunitinib [Sutent]. And then this year, we got the nivolumab/cabozantinib and the CLEAR study of lenvatinib and pembrolizumab. And then lastly, of course, we still have the cabozantinib monotherapy approved as first line for patients.

It’s been a historical problem because nivolumab/ipilimumab has held sway for quite a while. And then pembrolizumab/axitinib came in, looked promising, and a lot of people switched to it. I’ve done a number of focus groups, and most doctors have been using pembrolizumab/axitinib, and some still like nivolumab/ipilimumab because of the long-term complete responses. I continue to see my patients who’ve been in long term complete response. It’s pretty remarkable; these are people who had lots of cancer and are [now] off all treatment, cancer free. And now we have these 2 new combinations, nivolumab/cabozantinib and lenvatinib/pembrolizumab, both of which are approved up front. And most people don’t have experience with lenvatinib and pembrolizumab. Most of us have experience with pembrolizumab and cabozantinib, but we use that as second line. So we know that lenvatinib and pembrolizumab have just recently been approved; very few doctors have used that combination. Aside from just being approved and not on pathway up until just recently, the dose of lenvatinib has been very high. And because the dose is high, there’s been some reticence on the part of oncologists to embrace lenvatinib at the 20-mg-per-day dose. Not that that’s the wrong dose. It’s just we were told that it was 18 mg, and that you can dose reduce; 20 mg is a big dose, and hypertension and diarrhea and other things are not necessarily easy to handle in the outpatient setting.

To summarize, there’s been a new kid on the block—that’s lenvatinib and pembrolizumab. And the uptake has been relatively slow because there are very good alternatives. However, the CLEAR study is very impressive. It’s got a 71% response rate with long [progression-free survival], 23.9 months.2 So all of us are going, “Geez, maybe we should try that.” And I for one am waiting for my next patient who’s willing to be treated [with this regimen], understanding that I’m going to have a learning curve. But I also got to realize that my nurses have to be ready to deal with the [adverse] effects and [that] I’m going to have to be careful.

Some of these regimens have led to real-world studies. Specifically, there was one from US Oncology of lenvatinib and everolimus (Afinitor) that you worked on.3 Can you speak to those results at all?

That is an interesting study, suggesting that lenvatinib and everolimus [are] better than sunitinib, but not better than lenvatinib and pembrolizumab. So I don’t think it’s going to get a lot of play because everolimus adds some toxicity to the lenvatinib. And I don’t see [it going] anywhere. If you’re going to use sunitinib, you should use lenvatinib and everolimus. And if you’re going to use lenvatinib and everolimus, you should use pembrolizumab and lenvatinib. It was a nice idea, but it doesn’t lead anywhere. It was more done for regulatory purposes, I think.

This year at IKCS, there were a bunch of studies exploring lenvatinib in other combinations, some doublets, some triplets. Can you speak to any of these trials in progress?

Yes, lenvatinib is a very effective drug in a number of conditions. Obviously, it’s already been approved in hepatocellular [carcinoma]. It’s been approved in combination with pembrolizumab in endometrial [carcinoma]. It’s going to be studied in non–small cell lung cancer. It’s underway in bladder cancer. It’s a very promising agent. And I expect it will become a multibillion-dollar drug in a variety of diseases. One of my friends happens to work for Eisai. They’re looking at about 10 different indications for the drug in a variety of malignancies.

1. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. Updated August 11, 2021. Accessed December 13, 2021. https://bit.ly/31LwFU5

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. Vogelzang NJ, Monnette AM, Wang Y, et al. Real-world clinical effectiveness of lenvatinib/everolimus in a heavily pretreated advanced/metastatic renal cell carcinoma population in the US community oncology setting. 

2021;19(6):P531-P539. doi:10.1016/j.clgc.2021.05.002

In an interview with Targeted Oncology, Nicholas J. Vogelzang, MD, discussed how the treatment landscape has changed for renal cell carcinoma and the continuing promise of lenvatinib.

Promise of Lenvatinib Excites in the RCC Landscape

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.

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

Nivolumab (Opdivo) in combination with PARP inhibitor rucaparib (Rubraca) showed a significant survival benefit in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) who have homologous recombination deficiency (HRD) positivity, according to results from a final analysis of a cohort from the phase 2 CheckMate 9KD trial (NCT03338790).

Both radiographic progression-free survival (rPFS) and overall survival (OS) were longer among patients with HRD positivity compared with the overall cohort population and patients with negative or not-evaluable HRD status. Objective response rates (ORR) and prostate-specific antigen (PSA) response rates were highest among patients with mutations in 

1/2. Findings were detailed in a poster presentation during the 28th Annual Prostate Cancer Foundation (PCF) Scientific Retreat.

“In this cohort with chemotherapy-naïve metastatic CRPC, nivolumab with rucaparib showed clinical efficacy in patients with HRD-positive tumors, with noteworthy activity in those harboring BRCA mutations,” said Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine and coleader of Cancer Signaling Networks at Yale Cancer Center in New Haven, Connecticut.

The multicohort CheckMate 9KD trial looked at combinations with nivolumab in patients with mCRPC who were undergoing ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone analog or bilateral orchiectomy and had documented progression. Patients had an ECOG performance status of 0 or 1 and had no prior treatment with drugs targeting T-cell costimulation or immune checkpoint pathways.

Patients in cohort A received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg twice daily. Patients who had received 1 to 2 prior taxane chemotherapy regimens and up to 2 novel hormonal therapies were in cohort A1; patients who were not candidates for or who refused immediate chemotherapy and who had received 1 to 2 prior novel hormonal therapies prechemotherapy were in cohort A2.

Patients in Cohort B were chemotherapy-naïve but eligible for docetaxel and had received up to 2 novel hormonal therapies for prechemotherapy mCRPC. They received nivolumab and docetaxel.

Patients in Cohort C received prior abiraterone (Zytiga) for prechemotherapy mCRPC without prior enzalutamide or apalutamide (Erleada) and were not candidates for or refused immediate chemotherapy. They received nivolumab plus enzalutamide (Xtandi).

Coprimary study end points were ORR and PSA response rate, defined as the proportion of patients with a 50% or higher decrease in PSA from baseline. Secondary end points were rPFS, OS, time to objective response, duration of objective response, time to PSA progression, and safety. All efficacy end points were assessed in the overall treated population as well as in patients with HRD-positive tumors. HRD status was determined by tissue and plasma assays.

The PCF poster presentation focused on patients in cohort A2. Petrylak explained that the combination was explored in this patient population because PARP inhibitors increase cellular DNA damage in tumors with DNA repair defects, which leads to genomic instability and cell death.

Cohort A2 included 71 patients who were treated with the combination of nivolumab and rucaparib. Patients were a median of 73 years (range, 51-87). The majority of patients (57.7%) had an ECOG performance status of 1 and a Gleason score above 7 (54.9%). The median time since diagnosis was 4.1 years (range, 0.4-19.6). Most patients did not have visceral metastases (67.6%), but it was not reported in 8.5%. HRD positivity was positive in 47.9%, negative in 50.7%, and not evaluable in 1.4%. Prior novel hormonal therapy included abiraterone only in 60.6%, enzalutamide only in 23.9%, and both in 14.1%.

Patients in this cohort were followed for a median of 17.5 months. The median duration of therapy was 4.6 months for nivolumab and 5.5 months for rucaparib.

At data cutoff, 91.5% of patients had discontinued all treatment due to disease progression in 60.6% and drug toxicity in 11.3%. Four patients were still on treatment at cutoff.

The ORR in all evaluable patients (n=39) was 15.4% (95% CI, 5.9%-30.5%), which consisted of all partial responses. Stable disease (SD) was achieved in 66.7% of patients. The ORR in HRD negative or not-evaluable patients (n=19) was 5.3% (95% CI, 0.1%-26.0%), and 78.9% of patients had SD.

In HRD-positive patients (n=20), the ORR was 25.0% (95% CI, 8.7%-49.1%) and 55.0% had SD. In 9 patients with 

1/2 mutations, the ORR was 33.3% (95% CI, 7.5%-70.1%) and 55.6% had SD.

In all patients evaluable for PSA response (n=66), the response rate was 27.3% (95% CI, 17.0%-39.6%). In HRD negative/not-evaluable patients (n=35), the PSA response rate was 14.3% (95% CI, 4.8%-30.3%).

The PSA response rate was 41.9% (95% CI, 24.5%-60.9%) in patients with HRD positivity (n=31) and 84.6% (95% CI, 54.6%-98.1%) in patients with 

“The PSA response rate of 84.6% in patients with 

-positive tumors justifies further evaluation of this combination in patients with 

The median time to response was 2.0 months (range, 1.8-11.0) and the median time to PSA progression was 3.5 months (range, 2.8-6.2). The median duration of response was 7.1 months (95% CI, 3.5–not estimable [NE]).

The overall median rPFS was 8.1 months (95% CI, 5.6-10.9). Among patients with HRD negativity or not-evaluable HRD status, the median rPFS was 5.6 months (95% CI, 3.7-9.1) and 10.9 months (95% CI, 6.7-12.0) in patients with HRD positivity.

Median OS was 20.2 months (95% CI, 14.1-22.8) in the overall population. The median OS was 19.0 months (95% CI, 8.2-22.1) in patients with HRD negativity or not evaluable HRD status and 22.7 months (95% CI, 14.1-NE) in patients with HRD positivity.

Treatment-related adverse events (TRAEs) of any grade were reported in 90.1% of patients and were grade 3 or 4 in severity in 50.7%. The most common TRAEs of any grade were nausea (40.8%), anemia (32.4%), alanine aminotransferase (ALT) increase (28.2%), fatigue (28.2%), aspartate aminotransferase increase (25.4%), blood creatinine increase (21.1%), diarrhea (19.7%), decreased appetite (18.3%), vomiting (18.3%), and pruritis (15.5%). The most common grade 3/4 TRAEs were anemia in 14.1% and ALT increase in 12.7%.

TRAEs led to discontinuation in 23.9% of patients, most commonly due to anemia and increased ALT. No treatment-related deaths were reported in cohort A2.

“Longer follow-up is needed to better characterize the clinical benefits of adding nivolumab to rucaparib for patients with HRD-positive, chemotherapy-naïve metastatic CRPC,” Petrylak concluded.

Petrylak DP, Perez-Garcia JL, Lacombe L, et al. CheckMate 9KD cohort A2 final analysis: nivolumab plus rucaparib for chemotherapy-naïve metastatic castration-resistant prostate cancer. Presented at: 2021 Prostate Cancer Foundation Scientific Retreat; October 28-November 5, 2021; virtual.

Survival benefit was shown with the combination of niraparib and rucaparib in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.

Nivolumab With Rucaparib Shows Survival Benefit in HRD+, Chemotherapy-Naïve mCRPC

In 2021, the FDA's crack down on accelerated approvals meant the removal of several immunotherapy indications from the US market.

In an editorial from FDA faculty members, Julia A. Beaver, MD; and Richard Pazdur, MD, they explained that in the 29 years that the accelerated approval pathway has existed, over 155 accelerated approvals for oncology drugs have been granted, but only 10 have been withdrawn due to an inability to confirm benefit of the drug in further trials.

An industry-wide evaluation of accelerated oncology drug approvals, where clinical benefit was not verified in subsequent confirmatory trials, called 10 immunotherapy indications into question this year.

These approvals have been dubbed “dangling” accelerated approvals. Each indication was granted an accelerated approval based on the findings from early-phase, often single-arm, studies using surrogate end points. These results were not confirmed, though, in confirmatory randomized phase 3 trials. The 10 approvals were granted between 2016 and 2019, yet their approvals withstood, oftentimes for years, after the results of confirmatory trials failed to show benefit.

Several developers responded by voluntarily withdrawing the drug from the market for the particular setting, but for other approvals, the Oncologic Drugs Advisory Committee (ODAC) was convened to debate whether continued approval was warranted for the dangling indications.

Voluntarily withdrawn indications included: nivolumab (Opdivo) as a treatment for patients with small cell lung cancer (SCLC) whose disease has progressed after platinumbased chemotherapy and at least 1 other line of therapy, which Bristol Myers Squibb announced in December 2020;2 durvalumab (Imfi nzi) for the treatment of adult patients with previously treated locally advanced or metastatic bladder cancer, which AstraZeneca withdrew on February 22, 2021;

 pembrolizumab (Keytruda) for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy and at least 1 other line of therapy, which was announced by Merck on March 1, 2021;

 and Roche’s atezolizumab (Tecentriq) for the treatment of patients with prior platinum-treated metastatic urothelial carcinoma, which was announced on March 8, 2021.

The FDA announced a 3-day public meeting of the ODAC, April 27-29, 2021, to discuss and reevaluate 6 indications to determine whether their accelerated approvals should be withdrawn: atezolizumab in combination with paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1; atezolizumab as treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy; pembrolizumab as treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy; pembrolizumab for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma with PD-L1 expression and disease progression on or after at least 2 prior lines of therapy, including fl uoropyrimidineand platinum-containing chemotherapy, and if appropriate, HER2-targeted therapy; nivolumab as treatment of patients with hepatocellular carcinoma (HCC) with prior treatment with sorafenib (Nexavar); and pembrolizumab for the treatment of patients with HCC previously treated with sorafenib.

Prior to the meeting, Arjun V. Balar, MD, director of the Genitourinary Medical Oncology Program at New York University Langone’s Perlmutter Cancer Center, told 

™, “The general take-home message is: Don’t view these ODACs as an indictment against immunotherapy. It is not. It is, rather, an opportunity for us to reset our expectations about it.”

During the meeting, oncology experts, industry members, patients with cancer, and members of the committee provided evidence of the efficacy and safety profiles of the agents in each setting as well as how the treatment landscape has changed since the initial approval to determine whether there is still a place for the indication. Of the 6 indications, the committee voted to maintain 4, with the exception of nivolumab in HCC, with a 5 to 4 vote, and pembrolizumab in gastric/GEJ adenocarcinoma, with a vote of 6 to 2.

“I believe the accelerated approval for pembrolizumab in the third-line setting was appropriate based on the modest response rates in KEYNOTE-059 [NCT02335411] and the clear unmet need, but the landscape… has clearly changed. It’s highly unlikely that, by third-line therapy, patients will [not] have received some form of immune checkpoint therapy previously,” said panelist Christopher H. Lieu, MD, associate director for clinical research and co-director of gastrointestinal (GI) medical oncology at the University of Colorado Medicine, when explaining his vote against pembrolizumab during the meeting.

Of note, ODAC voted unanimously in support of continued approval for pembrolizumab in HCC.

“[Patients with] HCC are sorely in need of treatment options, given the associated mortality. They need these options based on acceptability, convenience of treatment schedule, and reduced toxicities, especially in the era of the [COVID-19] pandemic,” said Cathy Eng, MD, FACP, FASCO, the David H. Johnson Chair in Surgical and Medical Oncology, coleader of the GI Cancer Research Program, and codirector of GI oncology at Vanderbilt-Ingram Cancer Center, during the meeting. “Decreasing treatment options is not approached to improve community outreach, and I do not believe that discontinuation of pembrolizumab’s accelerated approval as a second-line option is in the best interest of the patient.”

Following the ODAC meetings, 3 of the indications were voluntarily withdrawn. First was the pembrolizumab indication in gastric/GEJ adenocarcinoma, which Merck removed as of July 1, 2021,8 followed by the nivolumab indication in HCC, which was announced by Bristol Myers Squibb on July 23, 2021.9 Although the committee had voted 7 to 2 in favor of continued approval for the atezolizumab regimen in TNBC, on August 27, 2021, Roche announced that the indication was being voluntarily withdrawn.

Additionally, the FDA converted the accelerated approval for the pembrolizumab urothelial carcinoma indication to a full approval.

 During the ODAC meeting, panelists had voted 5 to 3 in favor of continued approval.

Later in the year, the FDA planned further ODAC meetings to discuss 3 more dangling indications. First was melphalan flufenamide (Pepaxto) for injection in combination with dexamethasone as treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody.

However, this meeting was canceled after the indication was voluntarily removed from the US market due to a phase 3 trial showing no benefit for melphalan flufenamide in terms of overall survival.

 Both the approval and withdrawal of the indication occurred within this year.

Next was a joint ODAC meeting planned for December 2, 2021, to discuss panobinostat (Farydak) capsules in combination with bortezomib (Velcade) and dexamethasone for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent, and vincristine sulfate liposome injection (Marqibo) for intravenous infusion for adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia in second or greater relapse or whose disease has progressed following 2 or more anti-leukemia therapies. However, this meeting was also canceled, and without explanation.

Accelerated Approval Pathway in Jeopardy?

The crack down on accelerated approvals comes in line with increased scrutiny on the pathway. Both the Institute for Clinical and Economic Review and Friends of Cancer Research have written white papers suggesting potential improvements to the pathway.

 Additionally, the Office of Inspector General of the US Department of Health and Human Services has pronounced its intent to reexamine FDA policies and procedures to assess how the pathway is implemented,

especially following the controversial accelerated approval of an Alzheimer drug, aducanumab (Aduhelm). The review is expected to occur in 2023.

The FDA and others defend the use of the pathway to fill areas of significant unmet needs but concede that improvement could still be made.

1. Beaver JA, Pazdur R. “Dangling” accelerated approvals in oncology. N Engl J Med. 2021;384(18):e68. doi:10.1056/NEJMp2104846 

2. Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer US indication. News release. Bristol Myers Squibb; December 29, 2020. Accessed November 30, 2021. https://bit.ly/2X5PVFK 

3. Voluntary withdrawal of Imfi nzi indication in advanced bladder cancer in the US. News release. AstraZeneca; February 22, 2021. Accessed November 30, 2021. https://bit.ly/3dPZimL 

4. Merck provides update on Keytruda (pembrolizumab) indication in metastatic small cell lung cancer in the US. News release. Merck; March 1, 2021. Accessed November 30, 2021. https://bit.ly/3e1ct4j 

5. Roche provides update on Tecentriq US indication in prior-platinum treated metastatic bladder cancer. News release. Roche; March 8, 2021. Accessed November 30, 2021. https://bit.ly/3d5kwe2 

6. FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA; March 11, 2021. Updated March 15, 2021. Accessed November 30, 2021. https://bit.ly/3lmMneP 

7. Meeting of the Oncologic Drugs Advisory Committee meeting announcement. FDA. April 29, 2021. Accessed November 30, 2021. https://bit.ly/2PyhdV1 

8. Merck provides update on Keytruda (pembrolizumab) indication in third-line gastric cancer in the US. News release. Merck; July 1, 2021. Accessed November 30, 2021. https://bit.ly/3jO1kGM 

9. Bristol Myers Squibb statement on Opdivo (nivolumab) monotherapy post-sorafenib hepatocellular carcinoma US indication. News release. Bristol Meyers Squibb; July 23, 2021. Accessed November 30, 2021. https://bit.ly/2UOBmZI 

10. Roche provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Roche; August 27, 2021. Accessed November 30, 2021. https://bit.ly/3o8HHLl 

11. FDA approves updated indication for Merck’s Keytruda (pembrolizumab) for treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck; August 31, 2021. Accessed November 30, 2021. https://bit.ly/2WEvhQk 

12. Cancelled October 28, 2021: meeting of the Oncologic Drugs Advisory Committee meeting announcement. FDA; October 22, 2021. Accessed November 30, 2021. https://bit.ly/3xGo2Fy 

13. Oncopeptides withdraws Pepaxto in US, scale down organization and focus on R&D. News release. Oncopeptides; October 22, 2021. Accessed November 30, 2021. https://bit.ly/3m7fdAB 

14. Cancelled: December 2, 2021: meeting of the Oncologic Drugs Advisory Committee meeting announcement. FDA. Updated November 23, 2021. Accessed November 30, 2021. https://bit.ly/3pbFGNT 

15. Strengthening the accelerated approval pathway: an analysis of potential policy reforms and their impact on uncertainty, access, innovation, and costs. Institute for Clinical and Economic Review. April 26, 2021. Accessed November 30, 2021. https://bit.ly/3xFew5B 

16. Optimizing the use of accelerated approval. Friends of Cancer Research. Accessed November 30, 2021. https://bit.ly/3d7vEaI 

17. Review of the FDA’s accelerated approval pathway. US Department of Health and Human Services. August 2021. Accessed November 30, 2021. https://bit.ly/3xN2A20