Nichole Tucker

The latest data from the phase 3 CLEAR study (NCT02811861) showed that with about 33 months’ follow-up, the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) continued to demonstrate an overall survival (OS) advantage vs single-agent sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC).

The lenvatinib/pembrolizumab combo also maintained benefits in progression-free survival and objective response rate vs sunitinib.

The updated results, which were shared at the 2022 International Kidney Cancer Symposium, also showed that the lenvatinib/pembrolizumab also maintained benefits in progression-free survival (PFS) and objective response rate (ORR) compared with sunitinib.

The PFS and OS benefits observed in the overall study population were also shown in certain subgroups. For example, patients with intermediate-/poor-risk advanced RCC favored lenvatinib and pembrolizumab vs sunitinib. Among favorable-risk patients, the median OS was not reached, and only a few OS events were seen in these patients.

Prior to the updated analysis results, lenvatinib plus pembrolizumab significantly improved PFS vs sunitinib in patients with advanced RCC (HR, 0.39; 95% CI, 0.32-0.49; 

 < .001). The combination also demonstrated a significant OS advantage compared with sunitinib (HR, 0.66; 95% CI, 0.49-0.88; 

 = .005). The ORR shown in the primary analysis of the CLEAR study was 71.0% in the lenvatinib plus pembrolizumab arm compared with 36.1% in the sunitinib arm (relative risk [RR], 1.97; 95% CI, 1.69-2.29; nominal 

CLEAR is a 3-arm trial of patients with advanced RCC who are treatment-naïve, presented with a Karnofsky performance score of ≥ 70, have measurable disease, and adequate organ function. Patients were randomized 1:1:1 to receive lenvatinib 20 mg once daily plus pembrolizumab 200 mg every 3 weeks, lenvatinib 18 mg once daily with everolimus (Afinitor) 5 mg once daily, or sunitinib 50 mg once daily. With patients stratified by disease risk and geographic location, PFS was the primary end point of the study. The secondary end points included OS, ORR, safety, and health-related quality of life. As exploratory end points, duration of response (DOR) and biomarkers were also assessed in the study.

The updated analysis focused on a comparison of the lenvatinib/pembrolizumab arm and the sunitinib arm. At baseline, patients had a median age of 64 years (range, 34-88) in the combination arm vs 61 years (range, 29-82) in the sunitinib arm. More than 55% percent of patient in each arm were European or North American, and the remainder were from other parts of the world. According to the Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Database Consortium (IMDC) grouping, the majority of patients in both arms had intermediate-risk disease, and 10% or less in each arm had poor risk disease. Thirty-one percent of the combination arm had favorable risk disease vs 34.7% of the monotherapy arm.

The median follow-up for the updated analysis was 33.7 months in the lenvatinib/pembrolizumab arm vs 33.4 months in the sunitinib arm. The 12-month PFS was 70.6% (95% CI, 65.3-75.2) with the combination vs 38.4% (95% CI, 32.4-44.3) with sunitinib. At 24 months, the PFS rate was 48.6% (95% CI, 42-54.3) with lenvatinib and pembrolizumab vs 22.6% (95% CI, 17.1-28.5) with sunitinib.

OS also continued to favor lenvatinib plus pembrolizumab with extended follow-up. The median OS was not reached in the combination arm nor in the sunitinib arm (HR, 0.72; 95% CI, 0.55-0.93). The 12-month OS rate observed with lenvatinib plus pembrolizumab was 91.4% (95% CI, 87.9-93.9) vs 80.2% (95% CI, 75.5-84.1) with sunitinib. At 24-months, the OS rate was 80.2% (95% CI, 75.5-84.1) with the combination vs 69.7% (95% CI, 64.4-74.3) with sunitinib.

Notably, both PFS and OS results in the MSKCC and IMDC risk groups also favored treatment with lenvatinib and pembrolizumab vs sunitinib. The extended follow-up analysis also looked at patients who received lenvatinib and pembrolizumab who completed 2 years of treatment. These patients had OS rate of 94.5% at 36 months.

An ORR of 71.0% (95% CI, 66.3-75.7) was seen with lenvatinib/pembrolizumab compared with 36.1% (95% CI, 31.2-41.1) in the sunitinib arm (RR, 1.97; 95% CI, 1.69-2.29). In the combination arm, the complete response rate was 17.2% vs 4.2% with sunitinib, and the partial response rate was 53.8% with the combination vs 31.9% with sunitinib. The median DOR was 26.0 months (95% CI, 22.2-41.4 months) with lenvatinib/pembrolizumab vs 14.7 months (95% CI, 9.4-16.8 months) with sunitinib.

According to the study investigators, the extended follow-up data from the CLEAR study demonstrated robust efficacy that has been maintained with longer follow-up. These data support the use of frontline lenvatinib and pembrolizumab as a standard of care for patients with advanced RCC.

1. Porta CG, Masatoshi E, Motzer RJ, et al. Updated efficacy of lenvatinib + pembrolizumab versus sunitinib in patients with advanced renal cell carcinoma in the CLEAR study. Presented at: 2022 International Kidney Cancer Symposium. November 3-5, 2022; Austin, TX.

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The updated results were shared at the 2022 International Kidney Cancer Symposium.

Lenvatinib/pembrolizumab survival benefit in kidney cancer sustained with longer follow-up

Pidnarulex could be a future option for patients with 

positive mCRPC who are resistant to treatment with FDA-approved PARP inhibitors.

The first patient has been dosed in the phase 1 REPAIR trial (NCT05425862) exploring the investigational combination of pidnarulex (CX-5461) and talazoparib (Talzenna) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Pidnarulex is an agent that targets the DNA repair irregularities in tumors with homologous recombination deficiency. The agent works by stabilizing DNA G-quadruplexes of cancer cells and interfering with the cell’s replication fork. Conclusively, pidnarulex leads to cancer cell death.

The FDA recently granted fast track designation to pidnarulex for the treatment patients with BRCA 1/2- and PALB2-positive ovarian or breast cancers. Considering that prevalence of BRCA 1/2-positive prostate cancer tumors, pidnarulex may have a role in the United States. Specifically, the agent could be a future option for patients with BRCA 1/2-positive mCRPC who are resistant to treatment with FDA-approved PARP inhibitors.

REPAIR has an open-label, multicenter, dose-escalation design. The targeted enrollment goal is 48 patients and the estimated primary completion date is July 12, 2024.

During the study, patients with mCRPC will be given escalated doses of both pidnarulex and talazoparib to achieve the primary end point of determining the maximum-tolerated dose of pidnarulex, as well as the recommended phase 2 dose. Secondary end points that will be assessed during the study include safety, prostate specific antigen (PSA) response, radiographic progression-free survival (PFS), PSA PFS, overall survival, duration of response, and treatment discontinuation rate.

Patients are eligible to enroll in REPAIR if they are 18 years of age or older with histologically or cytologically confirmed mCRPC, an ECOG performance status of at least 1, and adequate bone marrow, hepatic, and renal function. Further, patients must have a PSA of ≥ 5ng/ml at the time of registration, as well as serum testosterone levels ≤ 50ng/dL within 28 days prior to cycle 1 day 1, and a life expectancy of at least 24 weeks.

Patients are also required to have progressed on a second-generation androgen receptor targeted therapy, received at least 1 prior line of chemotherapy, have progressive disease at the time of study entry, or have undergone prior surgical orchiectomy or chemical castration.

The study is actively recruiting patients for the first study site, Peter MacCallum Cancer Centre in Melbourne, Australia.

“Pidnarulex alone has shown efficacy in tumor cells resistant to PARPi in the preclinical studies. Therefore, we think pidnarulex demonstrates great potential as an alternative treatment for prostate cancer patients who have acquired resistance to PARPi or other chemotherapies,” Jin-Ding Huang, PhD, chief executive officer, Senhwa Biosciences, the developer of pidnarulex, stated in a press release.

1. Senhwa announces first patient successfully dosed in phase i study of pindnarulex in combination with Pfizer’s talazoparib for the treatment of prostate cancer. News release. October 31, 2022. Accessed November 1, 2022. https://www.senhwabio.com/en/news/20221031

2. Pidnarulex and talazoparib in patients with metastatic castration resistant prostate cancer (REPAIR). ClinicalTrials.gov. Updates October 28, 2022. Accessed November 1, 2022. https://clinicaltrials.gov/ct2/show/NCT05425862?term=CX-5461&draw=2&rank=3

Researchers hope to find synergistic effects with the combination of the ribosomal RNA synthesis inhibitor pidnarulex and the PARP inhibitor talazoparib.

Study explores novel combo of pidnarulex and talazoparib in mCRPC

Initial results from a phase 1/2 study (NCT03972657) showed dose-dependent antitumor activity with REGN5678 and the PD-1 inhibitor cemiplimab (Libtayo) in patients with metastatic castration-resistant prostate cancer (mCRPC), suggesting that REGN5678 may help overcome these tumors’ resistance to immune checkpoint therapy.

"In past clinical trials, metastatic castration-resistant prostate cancer has been largely unresponsive to PD-1 inhibition and immunotherapy in general, leaving patients with inadequate treatment options, a poor prognosis and an expected survival of one to two years depending on the treatment history," Mark Stein, MD, a trial investigator and associate professor of Medical Oncology at Columbia University Vagelos College of Physicians and Surgeons, stated in a press release. "These initial data provide the first clinical evidence indicating that a costimulatory bispecific antibody may synergistically combine with an anti-PD-1 agent such as Libtayo to enable activity against a tumor class previously resistant to anti-PD-1 immunotherapy. We look forward to further investigating the safety and efficacy of this combination."

To carry out the dose-escalation assessment, patients in cohorts 1-5 were treated with a low-dose REGN5678 and cohorts 6-8 received higher doses.

Evidence of dose-dependent antitumor activity was seen within 6 weeks among patients treated with higher doses of REGN5678 plus cemiplimab. In cohort 6, 1 out 4 patients achieved a 100% decrease in PSA and a complete response (CR) in target lesions per RECIST v1.1. Although the patient discontinued treatment due to a grade 3 adverse event (AE), the patient’s condition was resolved with treatment. Further, the 100% decrease in PSA and CR in target lesions has been maintained for approximately 10 months to date, according to the investigators’ assessment.

In cohort 7, 3 out of 8 patients had decreases in PSA of > 99%, 44%, and 22% resulting from REGN5678 and cemiplimab. Grade 3 AEs (aseptic encephalitis and seizure) occurred in 2 of the patients. Both cases have been resolved.

Three out of 4 patients who were treated in cohort 8 showed PSA reductions in PSA of > 99%, > 99%, and 82%. Of those with > 99% PSA decreases, 1 experienced grade 3 mucositis, which has since been resolved. The other patient experienced grade 3 acute inflammatory demyelinating polyradiculopathy, which is ongoing.

Patients treated in cohorts 1-4 showed almost no sign of antitumor activity. One patient out of 17 demonstrated a 22% decrease in PSA. The lack of benefit shown in the low-dose cohorts was consistent with the approximate 6% response rate reported in other trials in which anti-PD1 monotherapy was administered.

Overall, no grade ≥ 3 immune-related adverse events (irAEs) were observed in patients without antitumor activity, and the occurrence of irAEs appeared to be associated with antitumor activity. The safety result was consistent with previous studies in which irAEs were observed with higher doses of anti-PD1 monotherapy. No cases of grade 4 irAEs or grade ≥ 2 cytokine release syndrome have been observed in the trial. One death occurred, which was unrelated to treatment. As the trial continues, investigators are following standard management practice for checkpoint inhibitors to treat patients who experience irAEs.

The first-in-human, open-label study follows a dose-escalation and dose-expansion design. The goal of the study is to evaluate the safety, efficacy, and pharmacokinetics of REGN5678 monotherapy and REGN5678 in combination with cemiplimab 350 mg. In the dose-escalation portion of the study, there is a 3-week safety lead-on of REGN5678 monotherapy prior to the addition of cemiplimab. All treatment in the study is continued until disease progression intolerable adverse events (AEs), withdrawal or consent, or until the study criterion are met.

Safety- and tolerability-related primary end points being assessed in study the include the incidence and severity of treatment-emergent AEs, AEs of special interest, and serious AEs, as well as the number of grade 3 laboratory abnormalities, and the incidence of dose-limiting toxicities. Other primary end points explored in the study are concentration of REGN5678 in serum over time, concentration of REGN5678 in combination with cemiplimab in serum over time, and objective response rate per modified Prostate Cancer Working Group 3 (PCWG3) criteria.

The study is also evaluating the percentage of patients with ≥ 90% decline of PSA, percentage of patients who have achieved conversion of circulating tumor cell count from baseline of ≥ 5 cells/7.5mL to < 5 cells/7.5mL, the presence or absence of antibodies against REGN5678, and the presence or absence of antibodies against cemiplimab as secondary end points.

To be include in the study, patients must have histologically or cytologically confirmed prostate cancer without pure small cell carcinoma and mCRPC with PSA value at screening that measures ≥ 4 ng/mL and has progressed within 6 months prior to screening. All patients must be previously treated with ≥ 2 lines of systemic therapy approved in the metastatic and/or castration-resistant setting along with androgen deprivation therapy.

"Through extensive preclinical research, we hypothesized that augmenting T-cell costimulation alongside PD-1 inhibition could be a key to turning immunologically 'cold' tumors 'hot'," said George D. Yancopoulos, MD, PhD, president and chief scientific officer at Regeneron, in the press release.1 "These preliminary data for our PSMAxCD28 costimulatory bispecific provide the first clinical evidence supporting the promise of our broader pipeline of costimulatory bispecifics in diverse solid tumors and hematological malignancies. By combining these costimulatory bispecifics with Libtayo or our CD3 bispecifics, we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers.”

1. A novel costimulatory bispecific antibody shows encouraging anti-tumor activity when combined with PD-1 inhibitor Libtayo® (Cemiplimab) in advanced metastatic castration-resistant prostate cancer (mCRPC). News release. Regeneron Pharmaceuticals, Inc. August 3, 2022. Accessed August 3, 2022. https://bit.ly/3SrujyS

2. Study of REGN5678 (Anti-PSMAxCD28) with cemiplimab (Anti-PD-1) in patients with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated March 9, 2022. Accessed August 3, 2022.

The costimulatory bispecific antibody REGN5678 may alleviate resistance to immune checkpoint inhibition historically observed in prostate tumors. 

Novel agent may help overcome PD-1 inhibitor resistance in mCRPC

In a recent interview, Joaquim Bellmunt, MD, PhD, associate professor, Medicine, Harvard Medical School and director, Bladder Cancer Program, Beth Israel Deaconess Medical Center, discussed long-term data from the phase 3 JAVELIN Bladder 100 trial of frontline maintenance avelumab (Bavencio) in patients with metastatic urothelial cancer (mUC) who received first-line chemotherapy.

The interview took place earlier this year during the 2022 GU Cancers Symposium, where the updated findings were shared. Bellmunt also previews additional data from the JAVELIN Bladder 100 trial that will be presented at the 2022 ASCO Annual Meeting.

As a recap, what was observed in the primary analysis of the JAVELIN Bladder 100 trial?

: The primary analysis of survival showed that the median overall survival in the patients who receive avelumab maintenance was 21.4. And in the best supportive care arm, it was 14.3 months. That means a 7-month improvement in median overall survival with a hazard ratio of 0.69.

The first analysis was done in October 2019. And the analysis presented at AUA was after at least 2 years of follow-up with a data cutoff of June 2021. So, with that, we see that the long-term follow-up of this trial is confirming the results that were already published in the 

How was the long-term analysis of the JAVELIN Bladder 100 trial carried out?

This trial was designed in patients with metastatic bladder cancer that were receiving treatment with platinum gemcitabine or carboplatin/gemcitabine and if the patients didn't progress, meaning if the patients were able to obtain partial response, stable disease, or complete response, then the patients were randomized to receive maintenance avelumab plus best supportive care.

With this recent analysis, what we have seen is that the median overall survival in the avelumab maintenance is 23.8 months, and in the best supportive care arm it is like 15.0 months, meaning an 8-month difference in the median. The hazard ratio is more or less the same at 0.76, and the benefit has been seen across different subgroup of patients. Independent of patients responding or not responding, all patients benefited from receiving avelumab maintenance.

The benefit was seen in survival and was also seen in progression-free survival. So, in this updated analysis, the PFS in the overall population of patients receiving avelumab was 5.5 months, it was 2.1 months in patients receiving best supportive care. So, a substantial PFS prolongation was seen in these patients receiving avelumab maintenance.

Another analysis being presented during AUA is around subsequent therapy the patients received because obviously, we know that a particular therapy sometimes impacts overall survival. And what we saw in the analysis was that in patients that were assigned receive avelumab maintenance, 11.4% of patients received subsequent therapy with a PD-1 or PD-L1 inhibitor while in the best supportive care 53% of patients received a PD-1/PD-L1 inhibitor. This means that giving maintenance avelumab sooner provides a survival advantage.

What did longer follow-up teach you about frontline maintenance avelumab treatment in this patient population?

We now know that the percentage of patients who are alive in this trial or at years is 49.8% in the avelumab maintenance population versus 38.4% in the best supportive care arm. We haven't seen unexpected adverse events, so it confirms the safety of this type of approach when using switch maintenance to manage patients who do not progress to chemotherapy in the first line.

These results support the recommendation of avelumab first-line maintenance as a standard of care in urothelial cancer, patients with metastatic disease receiving chemotherapy with platinum-based therapy, carboplatin, or cisplatin, and those who are not progressing. So, this is a new standard of care when managing metastatic bladder cancer patients.

So, now the concept of avelumab maintenance as the standard of care has been included in all the guidelines.

What other type of sub analysis will be important from this study?

Upcoming at the ASCO 2022 Annual Meeting, we are going to update additional data on what's the role of second-line therapies if the patient will receive chemotherapy as rescue therapy because this is something that we don't know presently.

What do we do after the patient has received chemotherapy, followed by maintenance avelumab and they progress? Some guidelines say the next step is enfortumab vedotin, and in fact, there is very limited data on that. In the analysis that is going to be presented at ASCO, we are going to see the results of a patient receiving rechallenge with chemotherapy because those patients have already responded to first-line chemotherapy, or at least they have not progressed. The patients have a holiday period where they receive avelumab maintenance and then when they progress, some patients can receive again platinum-based therapy. And this is something that we don't know, all these data need to be collected. So, what's the outcome in these patients, either it's good to receive subsequent chemotherapy, or maybe there is a chance to give a targeted therapy, but we presently don't know.

We know that the blood cancer landscape is changing so quickly, we are waiting for new trials in the first line combining immunotherapy with an antibody-drug conjugate that may be changing the future in the way that we treat first-line metastatic patients. As more data are being analyzed from these trials, we will be able to design the best strategy in terms of how to sequence therapy in patients with bladder cancer in order to provide improved survival while preserving the quality of life. That's a very important thing.

1. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. 

. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487

“This is a new standard of care when managing metastatic bladder cancer patients,” says Joaquim Bellmunt, MD, PhD.

Nichole Tucker

Articles

Lenvatinib/pembrolizumab survival benefit in kidney cancer sustained with longer follow-up

Study explores novel combo of pidnarulex and talazoparib in mCRPC

Novel agent may help overcome PD-1 inhibitor resistance in mCRPC

Expert reviews long-term maintenance avelumab results in urothelial cancer