Chris Ryan

Inter- and intra-reader reproducibility results with the novel PET imaging agent 18F-rhPSMA-7.3 showed high concordance when used in patients with biochemically recurrent prostate cancer, according to findings from the phase 3 SPOTLIGHT trial presented at the 2022 Society of Nuclear Medicine and Molecular Imaging (SNMMI) Annual Meeting.

The overall inter-reader agreement for 18F-rhPSMA-7.3 PET/CT was above 75% and was highest for the pelvic lymph node region at above 87%. The overall intra-reader agreement was higher than 85%.

“Biochemically recurrent prostate cancer can be locally recurrent disease, metastatic disease, or both. Therefore, optimal assessment of the extent and location of recurrent prostate cancer is critical for clinical decision-making by physicians and patients,” Phillip Kuo, MD, PhD, Departments of Medical Imaging, Medicine, and Biomedical Engineering, University of Arizona, on behalf of the SPOTLIGHT study group, stated in a news release.

“Unfortunately, recurrence of prostate cancer is common. Conventional imaging, such as CT and bone scintigraphy, is often negative particularly when PSA is still low, so the demonstrated performance of PSMA-PET imaging fits an important unmet need. But no matter how good the radiotracer or scanner, reliable and consistent interpretation of PET imaging is foundational and has the potential to substantially impact patient care. These findings from the SPOTLIGHT study showed high inter-reader and intra-reader agreement for interpretation of 18F-rhPSMA-7.3 PET/CT scans in the setting of biochemical recurrence. Such high reproducibility, particularly for extra-prostatic regions, is clinically valuable, due to the potential of these findings to influence patient management,” added Kuo.

The multicenter, single-arm SPOTLIGHT (NCT04186845) enrolled male patients who were at least 18 years of age and received prior curative intent treatment for localized prostate cancer. Patients were required to have elevated PSA that could indicate biochemical recurrence and be eligible for salvage therapy. 18F-rhPSMA-7.3 was administered at a dose of 296 MBq/8 mCi, and PET/CT scans were given between 50 and 70 minutes following injection. Scans were then evaluated by 3 blinded central readers. The Standard of Truth was histopathology or confirmatory conventional imaging. Biopsies took place with 60 days following PET scans, and confirmatory imaging was conducted within 90 days.

The analysis presented at SNMMI assessed overall image interpretation agreement between the 3 blinded readers as well as image interpretation agreement for the regions of the prostate/prostate bed, pelvic lymph nodes, and other (extra-pelvic) sites (lymph nodes outside pelvis, soft tissue/parenchyma, and bones).

Agreement was high across all readers. When assessed by region, prostate/prostate bed reproducibility was lower than reproducibility for other regions; however, the study researchers noted that, “the high reproducibility for extra-prostatic regions is clinically valuable due to the potential of these findings to influence patient management.”

Data from the SPOTLIGHT trial previously presented at the 2022 AUA Annual Meeting showed that compared with baseline conventional imaging, PET imaging with 18F-rhPSMA-7.3 frequently led to post-scan disease upstaging in men with prostate cancer recurrence.

Among 250 of 366 men in the efficacy analysis population who had negative baseline conventional imaging, 18F-rhPSMA-7.3 showed a correct detection rate between 45% and 47%, which is the percentage of patients scanned with at least one true positive PET finding compared with the Standard of Truth of histopathology or confirmatory conventional imaging. Notably, upstaging results were found to vary based on prior treatment and anatomical region.

Prior data from the SPOTLIGHT trial were also presented at the 2022 Genitourinary Cancers Symposium, showing that the overall detection rate in patients who had an evaluable 18F-rhPSMA-7.3 scan was 83% by majority read.

1. Blue Earth Diagnostics Announces Reader Reproducibility Results from Phase 3 SPOTLIGHT Trial of Investigational PET Imaging Agent 18F-rhPSMA-7.3 in Biochemical Recurrence of Prostate Cancer. Published online June 15, 2022. Accessed June 15, 2022. https://bwnews.pr/3O8Yto0

2. Fleming MT. Impact of 18F-rhPSMA-7.3 PET on upstaging of patients with prostate cancer recurrence: results from the prospective, phase 3, multicenter, SPOTLIGHT study. Presented at: 2022 AUA Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract PLLBA-02.

3. Schuster DM. Detection rate of 18F-rhPSMA-7.3 PET in patients with suspected prostate cancer recurrence: results from a phase 3, prospective, multicenter study (SPOTLIGHT). J Clin Oncol. 2022(suppl 6):9. doi:10.1200/JCO.2022.40.6_suppl.009

Articles

“These findings from the SPOTLIGHT study showed high inter-reader and intra-reader agreement for interpretation of 18F-rhPSMA-7.3 PET/CT scans in the setting of biochemical recurrence,” said Phillip Kuo, MD, PhD. 

Reader reproducibility high with 18F-rhPSMA-7.3 image interpretation in prostate cancer

Compared with baseline conventional imaging, PET imaging with 18F-rhPSMA-7.3 frequently led to post-scan disease upstaging in men with prostate cancer recurrence, according to the latest data from the phase 3 SPOTLIGHT trial presented at the 2022 AUA Annual Meeting.

Among 250 of 366 men in the efficacy analysis population who had negative baseline conventional imaging, 18F-rhPSMA-7.3 showed a correct detection rate between 45% and 47%, which is the percentage of patients scanned with at least one true positive PET finding compared with the Standard of Truth of histopathology or confirmatory conventional imaging. Notably, upstaging results were found to vary based on prior treatment and anatomical region.

“We have hoped to have another option [to evaluate] patients for PSA [prostate specific antigen] recurrences, whether it was those with localized disease post prostatectomy or radiation therapy, [in addition to] what we can [currently] provide. We can find these tumor recurrences and options for treatment to salvage [these patients] better and earlier, and that is huge to both physicians and, most importantly, our patients,” said presenting author Mark Fleming, MD, Virginia Oncology Associates, US Oncology Research.

18F-rhPSMA-7.3 is an investigational prostate‐specific membrane antigen (PSMA)–targeted radiohybrid (rh) PET imaging agent. The agent has a longer half-life, a scope for larger batch productions, and improved spatial resolution in PET images compared with gallium 68.

Prior data from SPOTLIGHT (NCT04186845) presented at the 2022 Genitourinary Cancers Symposium showed that the overall detection rate in patients who had an evaluable 18F-rhPSMA-7.3 scan was 83% by majority read.

SPOTLIGHT enrolled male patients who were at least 18 years of age and received prior curative intent treatment for localized prostate cancer. Patients were required to have elevated PSA that could indicate biochemical recurrence and be eligible for salvage therapy.

18F-rhPSMA-7.3 was administered at a dose of 296 MBq/8 mCi, and PET/CT scans were given between 50 and 70 minutes following injection. Scans were then evaluated by 3 blinded central readers. The Standard of Truth was histopathology or confirmatory conventional imaging. Biopsies took place with 60 days following PET scans, and confirmatory imaging was conducted within 90 days.

Of the 420 patients who consented for the trial, 391 received 18F-rhPSMA-7.3, of which 389 underwent an evaluable PET/CT scan. Furthermore, 366 patients had sufficient data to determine Standard of Truth; these patients comprised the efficacy-evaluable population. Specifically, 69 patients had Standard of Truth determined by histopathology compared with imaging in 297 patients.

In this population, the mean age was 68.4 years (range, 43-85). The median PSA was 1.27 ng/mL (range, 0.03-134.6), and most patients had a Gleason grade group of 3 (30%).

Additional data showed the 18F-rhPSMA-7.3 detection rate was 88% compared with a correct detection rate of 57%.

In patients with negative baseline conventional imaging in the prostate bed region, between 3.5% and 8.0% of patients post prostatectomy showed true positive detections compared with between 39% and 41% of patients post radiation therapy.

In patients with negative baseline conventional imaging in the pelvic lymph node region, between 18% and 21% of patients post prostatectomy showed true positive detections vs 6.5% of patients post radiation. In patients with negative baseline conventional imaging in the extra-pelvic region, between 21% and 26% of patients post prostatectomy showed true positive detections vs between 20% and 30% of patients post radiation.

“It was very interesting for me, as you look closer to the data, that patients who had prostatectomy [were] different than patients who had radiation in the sites of disease,” Fleming said.

Based on the updated data from SPOTLIGHT, 18F-rhPSMA-7.3 could represent a way to better define sites of disease recurrence and identify salvage therapies for the right patients.

“[SPOTLIGHT] showed that we are able to upstage patients [with 18F-rhPSMA-7.3], that we are able to find disease that was missed [by conventional imaging] and gave a false sense of reassurance to patients that they didn’t have recurrence of the disease,” Fleming concluded.

Fleming MT. Impact of 18F-rhPSMA-7.3 PET on upstaging of patients with prostate cancer recurrence: results from the prospective, phase 3, multicenter, SPOTLIGHT study. Presented at: 2022 AUA Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract PLLBA-02.

Blue Earth Diagnostics announces additional results from phase 3 SPOTLIGHT trial of investigational PET imaging agent 18F-rhPSMA-7.3 in biochemical recurrence of prostate cancer. News release. Blue Earth Diagnostics. May 13, 2022. Accessed May 13, 2022. https://bwnews.pr/3wu1Cr9

Schuster DM. Detection rate of 18F-rhPSMA-7.3 PET in patients with suspected prostate cancer recurrence: results from a phase 3, prospective, multicenter study (SPOTLIGHT). 

. 2022(suppl 6):9. doi:10.1200/JCO.2022.40.6_suppl.009

Compared with baseline conventional imaging, PET imaging with 18F-rhPSMA-7.3 frequently led to post-scan disease upstaging in men with prostate cancer recurrence, according to the latest data from the phase 3 SPOTLIGHT trial.

Novel PET imaging agent 18F-rhPSMA-7.3 increases upstaging in recurrent prostate cancer

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, Robert Dreicer, MD, shared his expert insight on the evolving standard of care in the treatment paradigm for patients with metastatic castration-sensitive prostate cancer (mCSPC).

According to Dreicer, deputy director, UVA Cancer Center, director, Solid Tumor Oncology in the Division of Hematology/Oncology, and a professor of medicine and urology, University of Virginia Health System, standard treatment in this setting for most patients should include androgen deprivation therapy (ADT) in combination with 1 or 2 other agents vs ADT therapy alone.

Evidence from clinical trials exploring ADT in doublets or triplets with various agents, such as chemotherapy or androgen receptor (AR) inhibitors, has demonstrated combination therapies provide more benefits than ADT alone, Dreicer said. He noted optimal treatment selection should be determined by disease and non-disease factors of each patient, not comparative trial evidence.

“It’s not to say that no patients should be managed with primary ADT,” Dreicer, deputy director, UVA Cancer Center, director, Solid Tumor Oncology in the Division of Hematology/Oncology, and a professor of medicine and urology, University of Virginia Health System, said in a presentation. “The reality is [ADT alone] should be the rare exception [rather] than the rule. It should not be the other way around, given the benefit that we’ve been seeing [with combinations].”

Four agents are currently approved for the treatment of patients with mCSPC. Docetaxel was approved based on findings from the phase 2/3 STAMPEDE trial (NCT00268476) and phase 3 CHAARTED trial (NCT00309985).

 Abiraterone acetate (Zytiga) received approval based on the results of the phase 3 LATITUDE (NCT01715285) and STAMPEDE trials.

 Additionally, apalutamide (Erleada) was approved based on data from the phase 3 TITAN trial (NCT02489318),

 and enzalutamide (Xtandi) earned approval based on findings from the phase 3 ARCHES (NCT02677896) and ENZAMET (NCT02446405) trials.

Defining mCSPC involves several factors, which can affect treatment decisions, Dreicer noted. Hormone- or castration sensitive does not always mean a patient is naïve to hormonal therapy. Additionally, mCSPC is a heterogeneous disease state, where it can be classified as de novo or recurrent metastatic disease. Additionally, mCSPC can be defined as oligometastatic or polymetastatic, and imaging can be conducted through conventional means with a CT scan or next-generation imaging with a PSMA-based PET/CT scan or use of fluciclovine F18 and other PET agents.

Furthermore, mCSPC can also be classified as high- or low-volume disease. High-volume disease features the presence of visceral metastases, plus 4 or more bone lesions with at least 1 beyond the vertebral bodies and pelvis.

 Moreover, high-risk disease can be identified in patients who have 2 of 3 of the following: a Gleason score of 8 or more; at least 3 lesions on the bone scan; and the presence of visceral metastases.

Treatment combinations with ADT backbones have demonstrated overall survival (OS) benefits across multiple trials, both in high-volume/high-risk and low-volume/low-risk disease, Dreicer said. “AR pathway inhibitors from a number of different compounds showed a profound impact on OS,” Dreicer added.

Chemohormonal therapy with ADT plus docetaxel produced OS benefits in both the CHAARTED and STAMPEDE trials. In CHAARTED, the addition of docetaxel elicited a median OS of 57.6 months vs 44.0 months with ADT alone (HR, 0.61; 95% CI, 0.47-0.80; 

 < .001).8 Furthermore, in STAMPEDE a median OS of 81 months (interquartile range [IQR], 41–not reached [NR]) was achieved with docetaxel plus ADT vs 71 months (IQR, 32-NR) with ADT alone (HR, 0.78; 95% CI, 0.66-0.93; 

However, long-term follow-up from CHAARTED demonstrated a bigger benefit of ADT plus docetaxel for patients with high-volume disease.3 For patients with high-volume disease, the median OS was 51.2 months for ADT plus docetaxel vs 34.4 months for ADT alone (HR, 0.63; 95% CI, 0.50-0.79; 

 < .001). Conversely, patients with low-volume disease had a median OS of 63.5 months with docetaxel plus ADT; the median OS was NR for ADT alone (HR, 1.04; 95% CI, 0.70-1.55; 

“As we talk about treatment selections, we don’t have a lot of ways to separate making treatment decisions, but there is, at least with [docetaxel], a way to decide who may be a great candidate,” Dreicer explained.

Abiraterone also demonstrated an OS benefit in LATITUDE and STAMPEDE. In LATITUDE, the OS for ADT plus abiraterone and prednisone was NR compared with 34.7 months for ADT plus placebo (HR, 0.62; 95% CI, 0.51-0.76; 

In STAMPEDE, the cohort treated with ADT plus abiraterone and prednisolone experienced 184 deaths compared with 262 in the ADT-alone group (HR, 0.63; 95% CI, 0.52-0.76; 

 < .001).4 Additionally, the cohorts of ADT plus docetaxel and ADT plus abiraterone and prednisolone produced a HR of 1.16 for OS (95% CI, 0.82-1.65; 

“Although this is not a formal statistical comparison, it does involve similar patients accrued over a frame of time and gives some confidence that you’re not picking 1 drug that is better or worse than the other,” Dreicer said.

Several factors affect therapeutic decisions for patients with mCSPC. Regarding clinical factors, fitness for chemotherapy, AR inhibitors, and abiraterone should be considered. Frailty and comorbidities can define a patient’s fitness for an AR inhibitor, and blood sugar, cardiac history, and liver disease can play a role in a patient’s fitness for abiraterone. Patients with low-volume disease are more suited for an AR inhibitor or abiraterone, and patients with high-volume disease could benefit from docetaxel, an AR inhibitor, or abiraterone, Dreicer noted.

Patient preference can also affect therapy decisions, Dreicer added. Duration of therapy, aversion to pills or chemotherapy, quality of life (QOL), and economics all play a role.

“We do have good long-term follow-up from many of these studies with regard to QOL,” Dreicer said. “Fortunately, these therapies can be safely administered without meaningful impact on QOL.”

Research continued into possible combinations with ADT with the addition of enzalutamide in ENZAMET.

 Notably, this trial stratified patients based on high- or low-volume disease, and prior treatment with docetaxel was permitted. Patients received either ADT plus enzalutamide or ADT plus bicalutamide, nilutamide, or flutamide. At 36 months, 80% (95% CI, 75%-83%) of patients in the enzalutamide arm were still alive compared with 72% (95% CI, 68%-76%) in the non-enzalutamide arm (HR, 0.67; 95% CI, 0.52-0.86; log-rank 

Other trials have explored the addition of a third agent to ADT and docetaxel. The phase 3 PEACE-1 trial (NCT01957436) evaluated 4 arms of patients with de novo mCSPC. Patients were randomized to either ADT and docetaxel alone; ADT and docetaxel plus abiraterone and prednisone; ADT and docetaxel plus radiotherapy; or ADT, docetaxel, abiraterone, prednisone, and radiotherapy.

 The abiraterone arm generated a median OS of 5.7 months (95% CI, 5.1–not evaluable [NE]) compared with 4.7 months (95% CI, 4.3-5.3) for the ADT and docetaxel alone arm (HR, 0.82; 95% CI, 0.69-0.98; 

The phase 3 ARASENS trial (NCT02799602) explored the addition of darolutamide (Nubeqa) to ADT and docetaxel vs ADT and docetaxel alone. Darolutamide reduced the risk of death by 32.5%, with that arm achieving a median OS that was NE (95% CI, NE-NE) compared with 48.9 months (95% CI, 44.4-NE) in the placebo plus ADT and docetaxel arm (HR, 0.68; 95% CI, 0.57-0.80; 

As more agents have been added to the ADT backbone, median OS has improved for this patient population. Based on the results from PEACE-1 and ARASENS, the survival rates for those triplets are expected to exceed ADT alone, ADT plus docetaxel, and ADT plus abiraterone, Dreicer said.

The progress that is being made with additional [treatment] intensification is real,” Dreicer said. “We are just going to have to figure out which of the patients make sense [for each regimen to determine optimal treatment].”

1. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. 

. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5

2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. 

. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657

3. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. 

. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174

4. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. 

. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900

5. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. 

. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307

6. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. 

. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799

7. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. 

. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835

8. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. 

. 2015;373(8):737-746. doi:10.1056/NEJMoa1503747

9. Sydes MR, Spears MR, Mason MD, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. 

. 2018;29(5):1235-1248. doi:10.1093/annonc/mdy072

10. Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with 

 metastatic castration-sensitive prostate cancer (mCSPC): first results of PEACE-1. 

. 2021;39(suppl 15):5000. doi:10.1200/JCO.2021.39.15_suppl.5000

11. Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. 

. 2022;40(suppl 6):13. doi:10.1200/JCO.2022.40.6_suppl.013

According to Dreicer, standard treatment in this setting for most patients should include androgen deprivation therapy (ADT) in combination with 1 or 2 other agents vs ADT therapy alone.

Dr. Dreicer on optimizing treatment for patients with mCSPC

Findings from the phase 3 LEAP-011 trial showed that the addition of lenvatinib (Lenvima) to frontline pembrolizumab (Keytruda) did not improve overall survival (OS) vs pembrolizumab alone in patients with advanced urothelial carcinoma who were ineligible for platinum-based chemotherapy.

Results from the placebo-controlled trial presented at the 2022 ASCO Genitourinary Cancers Symposium showed that the median OS in the lenvatinib arm was 11.8 months (95% CI, 9.1-15.1) vs 12.9 months (95% CI, 9.8-17.8) in the pembrolizumab plus placebo group (HR, 1.14; 95% CI, 0.87-1.48). The median PFS was 4.5 (95% CI, 4.0-6.0) versus 4.0 months, respectively (95% CI, 2.7-5.4) (HR, 0.90; 95% CI, 0.72-1.14).

“The antitumor activity observed with pembrolizumab plus placebo was consistent with previous results of pembrolizumab monotherapy in similar populations of patients who are cisplatin ineligible or who are ineligible for any platinum-based chemotherapy,” lead study author Yohann Loriot, MD, PhD, of Gustave Roussy, Cancer Campus, and University of Paris-Saclay in Villejuif, France, said during the presentation. “First-line pembrolizumab monotherapy remains the standard of care in the United States for patients who are ineligible for any platinum-based chemotherapy, regardless of PD-L1 status.”

Pembrolizumab is an approved first-line therapy for patients with advanced urothelial carcinoma who are ineligible for platinum-based chemotherapy. Results from the phase 2 KEYNOTE-052 trial (NCT02335424) demonstrated the ability of pembrolizumab to generate meaningful and durable responses in cisplatin-ineligible patients.

 Findings from KEYNOTE-052 served as the basis for the accelerated approval of the agent in this setting, which was subsequently converted to a full approval in August 2021 in a platinum-ineligible population.

When combined with pembrolizumab, lenvatinib showed promising early activity and manageable safety in previously treated patients with advanced urothelial carcinoma, regardless of PD-L1 status, based on data from the phase 1b/2 KEYNOTE-146 trial (NCT02501096).

The LEAP-011 trial aimed to examine this combination in the first-line setting for patients with histologically confirmed advanced or metastatic urothelial carcinoma. Patients were required to be ineligible for cisplatin-based chemotherapy and have tumors with a PD-L1 combined positive score (CPS) of 10 or higher, or be ineligible for any platinum-based chemotherapy, regardless of PD-L1 status. Other eligibility criteria included no prior systemic chemotherapy and an ECOG performance status between 0 and 2.

The double-blinded, 1:1 randomized study planned to enroll 694 patients and place 347 patients in both the lenvatinib and placebo cohorts. An interim analysis of OS and PFS was planned to follow 530 PFS events, or approximately 24 months after the first patient was randomized. However, an independent data monitoring committee, which reviewed safety data every 3 months, determined the benefit-to-risk ratio of lenvatinib plus pembrolizumab, based on OS, PFS, and overall response rate (ORR) data, warranted stopping enrollment for the trial.

Ultimately, 487 patients were enrolled, with 245 enrolled to the lenvatinib arm and 242 enrolled in the placebo arm. Patients either received 20 mg of oral lenvatinib once daily or placebo. All patients were administered 200 mg of intravenous pembrolizumab once every 3 weeks for up to 35 cycles.

The dual primary end points of the trial were OS and PFS based on RECIST version 1.1 criteria by blinded independent central review. Key secondary end points included ORR, duration of response (DOR), disease control rate, safety, and tolerability.

The median age of patients in the lenvatinib arm was 74 years (range, 43-93) compared with 73 years (range, 47-92) in the placebo arm. In the lenvatinib and placebo arms, respectively, most patients were male (69.0% vs 76.0%), and most were ineligible for any platinum agent with an ECOG performance status of 2 (80.0% vs 80.2%). The remaining patients were cisplatin ineligible with a CPS of at least 10 (20.0% vs 19.8%). Other baseline characteristics included lymph node–only disease (24.1% vs 21.1%), visceral disease (74.7% vs 76.4%), liver metastases (24.9% vs 26.0%), and hemoglobin of at least 10 g/dL (89.8% vs 87.6%).

The lenvatinib arm achieved an ORR of 33.1% compared with a 28.9% ORR in the placebo arm. Additionally, the lenvatinib group had a median DOR of 12.8 months (range, 1.2+ to 20.8+) compared with 19.3 months (range, 1.4+ to 21.9+) in the placebo group.

Treatment-related adverse effects (TRAEs) of any grade were observed in 87.6% of patients in the lenvatinib group and 69.0% of patients in the placebo group. Grade 3 to 5 TRAEs occurred in 51.0% of patients in the lenvatinib arm and 27.3% of patients in the placebo arm. Notably, 19.9% of patients in the lenvatinib arm discontinued any drug because of a TRAE vs 9.1% of patients in the placebo group. Specifically, 10.0% of patients in the lenvatinib arm and 5.0% of patients in the placebo arm discontinued pembrolizumab, 19.1% discontinued lenvatinib, 8.7% discontinued placebo, and 7.9% in the lenvatinib arm and 3.3% in the placebo arm discontinued both drugs.

The lenvatinib arm reported serious TRAEs in 22.4% of patients, and 6 patients died from a TRAE. The placebo arm reported serious TRAEs in 9.9% of patients, and 1 patient died due to a TRAE. The duration of treatment was 3.9 months (range, 0-23.4) and 3.8 months (range, 0-25.0) in the lenvatinib and placebo groups, respectively.

The most common TRAEs of any grade in the lenvatinib and placebo arms, respectively, were proteinuria (37.8% vs 18.6%), hypothyroidism (36.5% vs 7.0%), hypertension (34.9% vs 7.0%), diarrhea (20.7% vs 10.3%), decreased appetite (14.5% vs 5.8%), fatigue (14.5% vs 12.0%), increased lipase (12.0% vs 7.0%), asthenia (12.0% vs 5.0%), nausea (11.6% vs 8.3%), pruritus (11.2% vs 14.5%), dysphonia (10.8% vs 0.4%), and rash (10.0% vs 5.8%).

1. Loriot Y, Grivas P, de Wit R, et al. First-line pembrolizumab with or without lenvatinib in patients with advanced urothelial carcinoma (LEAP-011): a phase 3, randomized, double-blind study. 

. 2022;40(suppl 6):432. doi:10.1200/JCO.2022.40.6_suppl.432

2. Vuky J, Balar AV, Castellano D, et al. Long-term outcomes in KEYNOTE-052: phase II study investigating first-line pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer. 

. 2020;38(23):2658-2666. doi:10.1200/JCO.19.01213

3. Pembrolizumab (Keytruda): advanced or metastatic urothelial carcinoma. News release. FDA. May 19, 2017. Accessed February 18, 2022. https://bit.ly/3gTUI7f

4. FDA approves updated indication for Merck’s KEYTRUDA (pembrolizumab) for the treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck. August 31, 2021. Accessed February 18, 2022. https://bwnews.pr/3zCgh3N

5. Taylor MH, Lee CH, Makker V, et al. Phase Ib/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. 

. 2020;38(11):1154-1163. doi:10.1200/JCO.19.01598

The addition of lenvatinib to pembrolizumab did not improve overall survival in patients with advanced urothelial carcinoma. 

Chris Ryan

Articles

Reader reproducibility high with 18F-rhPSMA-7.3 image interpretation in prostate cancer

Novel PET imaging agent 18F-rhPSMA-7.3 increases upstaging in recurrent prostate cancer

Dr. Dreicer on optimizing treatment for patients with mCSPC

Lenvatinib falls short as add-on to pembrolizumab in urothelial carcinoma