Jason M Broderick

Padcev plus Keytruda outperformed chemotherapy when it came to overall survival and progression-free survival in frontline advanced bladder cancer treatment. 

Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) led to better overall survival (OS; time from treatment until death of any cause) compared with chemotherapy in patients with previously untreated locally advanced or metastatic (spread to other parts of the body) urothelial carcinoma, a type of bladder cancer, according to findings from the phase 3 EV-302 clinical trial.

Findings, which were presented at the 2023 

, showed that at a median follow-up of 17.2 months, treatment with Padcev plus Keytruda — a regimen the researchers referred to as “EVP” — reduced the risk of death by 53% versus chemotherapy.

The median OS was 31.5 months in the EVP arm compared with 16.1 in the chemotherapy arm. The OS benefit was observed regardless of whether patients in the control arm received cisplatin or carboplatin and was not impacted by PD-L1 status or existence of visceral metastases.

Treatment with the combination also led to a significant improved in progression-free survival (PFS; time from treatment until disease gets worse or patients die) versus chemotherapy. The median PFS was 12.5 months with EVP compared with 6.3 months with chemotherapy, translating to a 55% reduction in the risk of disease progression or death. The PFS benefit was sustained across all pre-specified subgroups, such as those defined by cisplatin eligibility, PD-L1 status and visceral metastases.

“This is the first time (in urothelial carcinoma) we've managed to beat chemotherapy in the first-line setting for overall survival, despite multiple previous attempts. (Padcev) and (Keytruda) showed significant decrease in the risk of death and a decrease in the risk of progression compared to chemotherapy. These results support (Padcev) plus (Keytruda) as a standard of care in this setting,” said lead study author Dr. Thomas B. Powles, director, Barts Cancer Centre at St. Bartholomew’s Hospital in London.

The open-label EV-302 trial included 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma with an ECOG performance status of 2 or lower, indicating that they can perform most of their daily tasks with minimal help, who were eligible for cisplatin- or carboplatin-containing chemotherapy. The median age in both arms was 69 years and about three-fourths of patients were male. The majority of patients in the trial were White, making up 69.7% and 65.3% of the EVP and control arms, respectively. About 97% of patients in both arms had an ECOG performance status of 0 or 1.

In the EVP arm, the primary tumor location was upper tract for 30.5% of patients and lower tract for 69.0%. The rates were 23.4% and 76.4%, respectively, in the chemotherapy arm. Fifty-four percent of patients in each arm were cisplatin eligible and 72% had visceral metastases. Regarding PD-L1 status, 58% of in each arm had high expression (combined positive score [CPS] ≥10), with the remaining 42% having low expression (CPS <10).

Patients were randomly assigned to receive standard of care chemotherapy consisting of gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (444 patients) or Padcev on days 1 and 8 and Keytruda on day 1 of 3-week cycles (442 patients). The maximum number of Keytruda cycles allowed was 35 and there was no maximum number of cycles for Padcev. The co-primary end points were OS and PFS.

The confirmed objective response rate (ORR; percentage of patients whose disease responded to treatment) was 67.7% in the EVP arm compared with 44.4% in the chemotherapy arm. The ORR in the EVP group consisted of a complete response (CR; meaning that there were no tracible signs of cancer after treatment) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8% and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8% and the PD rate 13.6%.

The median number of cycles received was 12 (range, 1-46) for EVP and six (range, 1-6) for chemotherapy. Overall, 67% of patients in the EVP arm and 45.7% of patients in the chemotherapy arm remained on study at the time of the analysis. In the EVP arm, 34.6% of patients discontinued treatment due to progressive disease compared with 16.4% of patients in the chemotherapy arm. Side effect-related discontinuations occurred in 21.9% and 14.0% of the two arms, respectively. Regarding subsequent immunotherapy in the chemotherapy arm, 59% received a PD-1/L1 inhibitor and 30% of patients received maintenance Bavencio (avelumab).

“The safety profile of EVP was generally manageable, with no new safety signals observed,” said Powles. “Hematological toxicity was more prominent with chemotherapy, while peripheral neuropathy, rash, and hyperglycemia are adverse events of special interest with EVP.”

The safety data showed that 56% of patients receiving EVP and 70% of patients in the chemotherapy arm experienced grade 3 or higher treatment-related side effects. Serious side effects occurred in 27.7% vs 19.6% of the two arms, respectively.

FDA granted an accelerated approval to Keytruda plus Padcev

 for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

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For the first time, a drug combination (Padcev plus Keytruda) outperformed frontline chemotherapy for patients with locally advanced or metastatic urothelial carcinoma. 

Padcev Plus Keytruda Reduces Risk of Death, Disease Progression in Advanced Bladder Cancer

The combination of Welireg (belzutifan) and Lenvima (lenvatinib) showed promising clinical activity with manageable toxicity in patients with advanced clear cell renal cell carcinoma (ccRCC) and disease progression after receiving a PD-1/L1 inhibitor and a VEGF-TKI, according to initial results from arm B5 of the phase 1/2 KEYMAKER-U03B study.

 showed that at a median follow-up of 6.9 months, a regimen combining Welireg and the VEGF-TKI Lenvima elicited an objective response rate (percentage of patients whose disease shrunk or disappeared as a result of treatent) of 50% among 24 patients who had received at least two follow-up scans after enrolling in the trial. All of the responses were partial responses, meaning that the disease got smaller, but did not disappear entirely.

Data from the phase 1/2 KEYMAKER-U03B study showed promising results for the use of Welireg plus Lenvima to treat patients with clear cell renal cell carcinoma. 

The clinical benefit rate (patients whose disease responded and was stable for six or more months) was 54% and the median duration of response was not reached. Nearly three-fourths (74%) of responders remained in response for 12 months or longer. One patient had progressive disease.

Among all enrolled patients, the median progression-free survival (average time from treatment until disease worsened) was 11.2 months and at six months, 55% of patients did not experience disease progression.

“Preliminary results…from arm B5 of KEYMAKER-U03B showed promising antitumor activity with (Welireg) plus (Lenvima) in patients with (clear cell renal cell carcinoma) that progressed on PD-1/L1 inhibitors and VEGF-TKIs, a population that has limited efficacious treatment options,” said first study author Dr. Laurence Albiges, from the Institut Gustave Roussy, Villejuif, France.

Overall, the multicenter, multi-arm, open-label, adaptive, phase 1/2 KEYMAKER-U03B study is exploring various treatment combinations in patients with heavily pretreated clear cell renal cell carcinoma who have progressed after receiving a PD-1/L1 inhibitor and a VEGF-TKI, either in combination or given in sequence. As of the cutoff date of Sept. 29, 2022, 32 patients had been enrolled in arm B5, 30 had been treated and 23 remained on treatment.

The median patient age was 60.5 years, 78% of patients were male, and 78% of patients had intermediate/poor IMDC risk disease. The ECOG performance status was 0 for 17 patients and 1 for 15 patients. Seventy-eight percent of patients had prior nephrectomy, which is the surgical removal of one or both of the kidneys.

Patients in arm B5 were treated with Welireg at 120 mg orally each day and Lenvima at 20 mg orally each day. Patients received a median of 3.5 treatment cycles (range, 1.0-13.0)

There were no new side effects compared with the safety profiles of Welireg and Lenvima reported in previous research.In the safety lead-in phase of the trial, only 1 of 10 evaluable patients had a dose-limiting toxicity, which was difficult or labored breathing (grade 1).

In the overall safety analysis, which included all 30 treated patients, 93% (28 patients) of patients experienced at least one treatment-related side effect. The side effects that occurred in at least 30% of patients were anemia (43%), fatigue (43%), hypertension (43%), proteinuria (33%), diarrhea (33%), nausea (33%) and decreased appetite (30%).

Moderate or severe (grade 3/4) side effects occurred in half (15) of the patients. The most common grade 3/4 side effects were hypertension (27%) and anemia (17%). Side effects led to one patient discontinuing both study drugs, two patients discontinuing Lenvima and two patients discontinuing Welireg. There were no deaths due to side effects.

The combination is being further examined in the phase 3 LITESPARK-011 study, which is evaluating Welireg plus Lenvima compared with Cabometyx (cabozantinib) in patients with advanced kidney cancer and disease progression after treatment with a PD-1/L1 inhibitor.

Nearly three-fourths of patients with clear cell renal cell carcinoma had a disease response lasting 12 months or longer after being treated with Welireg and Lenvima, study data showed. 

Welireg Plus Lenvima Has ‘Promising Antitumor Activity’ in Kidney Cancer Subset

Bavencio (avelumab) plus Inlyta (axitinib) proved to be an effective option for the neoadjuvant (presurgical) treatment of patients with high-risk, non-metastatic clear-cell renal cell carcinoma, a common type of kidney cancer, according to findings from the NeoAvAx trial presented at the 2022 ASCO GU Symposium.

In the phase 2 trial, neoadjuvant Bavencio/Inlyta induced a partial response in 12 (30%) of 40 patients. On average, patients’ primary tumors shrunk by 20%. Among patients with a partial response, 10 of 12 were disease-free at the study data cutoff.

At a median follow-up of 23.5 months, the average length of overall survival (OS; defined as how long patients live after treatment) and median disease-free survival (DFS; meaning that there are no signs of the disease) had not yet been reached since many study participants are still alive. No patients had progression of their primary tumor.

NeoAvAx is the first trial combining these types of drugs — Bavencio is an immune checkpoint inhibitor and Inlyta is a tyrosine kinase inhibitor — for this particular patient population. Since the findings were so promising, it could lead to future studies where the drug duo is compared to other standards of care for high-risk clear cell RCC.

“This is the first neoadjuvant trial reporting results from a combination of an immune checkpoint inhibitor and VEGFR-TKI for locally advanced high-risk RCC,” said lead study author Dr. Axel Bex, of the Netherlands Cancer Institute.“The DFS data are encouraging, supporting further evaluation, although currently there are no randomized neoadjuvant versus adjuvant (immune checkpoint inhibitor) trials or neoadjuvant versus adjuvant ICI/VEGFR-TKI combination (trials in this setting).”

Explaining the background of the NeoAvAx trial, Bex said, “Antibodies targeting PD-1/PD-L1 combined with VEGF inhibitors are a first-line standard of care for metastatic RCC. Neoadjuvant use of these combinations may lead to downstaging and reduce the risk of recurrence.”

Overall, there were 40 patients enrolled in the trial between May 2018 and October 2021.

The median patient age was 63 years and 70% of patients were male.

Researchers considered each patient’s World Health Organization (WHO) performance status, which ranks patients’ restrictions on a scale of 0 (no restrictions to daily life as a result of the disease/treatment) to 4 (completely disabled) and 5 (dead). The WHO performance status was 0 for 30 patients and 1 (restricted for strenuous activity but allowed to do light/sedentary work) for 10 patients.

Ninety percent of patients’ disease was classified as stage T3 or higher, indicating that the cancer has grown into major veins within the kidney or nearby tissue.

Across the population, 42.5% of patients were clinically node positive.

Patients in the trial received Inlyta at 5 mg twice daily and Bavencio at 10mg/kg every two weeks. The main goal of the study was partial response (cancer shrinking) at week 12. Secondary endpoints included DFS, OS, and safety, and biomarker analysis on sequential tissue was an exploratory end point.

Overall, 13 (32.5%) patients had disease recurrence and three patients died of disease.

Bex said there were no new side effects with the neoadjuvant regimen as compared with previously reported safety data for Inlyta and Bavencio.

The majority of side effects were considered mild or bothersome, but not serious or severe. There were six total grade 3 side effects, comprising one case each of high blood pressure, infusion-related reaction, fatigue, nausea, hand-foot syndrome (defined as redness, swelling and blistering on the palms of the hands and soles of the feet) and elevated liver function tests.

Addressing the safety profile of the subsequent surgery patients received after the neoadjuvant regimen, Bex said, “Surgical adverse events were as expected in this patient population with locally advanced RCC.”

Bex also summarized the findings from the exploratory biomarker analysis. Patients with a higher concentration of CD8+ T cells tended to have better outcomes. Now, the researchers are continuing to further investigate other tumor differences that may impact outcomes.

"Spatial transcriptomics of post-treatment primary tumor tissue revealed focal intratumoral differences in immune signatures and we are currently investigating this further to see whether this may be one of the reasons why these patients have recurrence,” Bex said.

Bavencio and Inlyta is currently Food and Drug Administration approved

 for the frontline treatment of patients with advanced RCC. The approval was based on results from the pivotal phase 3 JAVELIN Renal 101 trial, which showed that the combination was associated with a 31% reduction in the risk of disease progression or death compared with Sutent (sunitinib) in patients with advanced RCC that has not previously been treated.

In a recent clinical trial, treatment with Bavencio plus Inlyta produced promising outcomes in the presurgical treatment of patients with non-metastatic, clear cell renal cell carcinoma.

Drug Duo Sparks Encouraging Outcomes in Treatment of Clear Cell Kidney Cancer

Patients with metastatic castration-resistant prostate cancer (mCRPC) tend to have better outcomes if they are obese, according to findings recently presented at the 36th Annual European Association of Urology Congress. This so-called “obesity paradox” has also been previously noted in other genitourinary cancers as well.

In an analysis of nearly 1,600 patients enrolled across three phase 3 trials, the overall survival (OS) rate at 36 months was about 30% in obese patients, compared with 20% in overweight and normal weight patients. Statistical modeling showed that the overall risk of death was 4% lower in obese patients when evaluating BMI as a continuous variable, and 29% lower with BMI as a categorical variable.

A person is classified as obese, overweight or within normal weight by their body mass index (BMI), which is calculated by dividing their weight (in kilograms) by their height (in meters) squared. Groupings are:

The investigators also determined that the OS benefit was not caused by the higher chemotherapy dose received by patients with a higher BMI. They found no interaction between BMI subgroups and the dose of chemotherapy.

"Looking at patients with metastasis of prostate cancer, we found that obese patients are living longer. This means that BMI could be used to predict survival in these patients,” study investigator Dr. Nicola Fossati, a urologist at San Raffaele University, stated in a press release.

"This obesity paradox has been seen in some other cancers, possibly due to the relationship between tissue fat and cancer genomes, and more research is needed in this area. It's also possible that improved survival may be due to the interaction of chemotherapy with other drugs. Obese patients in this older age group tend to be taking medication for other conditions and we do not fully understand how these medicines interconnect,” added Fossati.

"Nevertheless, we would not recommend weight gain to anyone with this or another disease. Obesity is a risk factor for many cancers and other diseases and patients should always aim for a healthy BMI of 18 to 24."

The study enrolled 1,577 patients with mCRPC enrolled across three phase 3 randomized control trials: ASCENT2, MAINSAL and VENICE. The average patient age was 69 years and the median BMI was 28 mg/m2. The median follow-up for survivors was 12 months.

Beyond overall survival, the “obesity effect” was also observed with cancer-specific survival. Statistical modeling showed that the risk of cancer-related death was 6% lower in obese patients when evaluating BMI as a continuous variable, and 35% lower with BMI as a categorical variable.

"There are many possible explanations for the association of body weight with positive outcome in metastatic cancers,” said Dr. Peter Albers of Düsseldorf University, who chairs the EAU Scientific Congress Office, in the press release. “It might be that patients with higher BMI are able to tolerate the toxicity of the treatments and their side effects better; in prostate cancer it might be due to the protective impact of hormones found in tissue fat; and it is known that healthy men with slightly higher BMI have a higher overall life expectancy compared to very slim ones.”

"However, at the moment, these are just hypotheses. Further research is needed to identify the biological mechanism behind these different outcomes. Until that mechanism is proven, we can't recommend any change to treatment for patients with advanced prostate cancer," added Albers.

A version of this article was originally published on Urology Times as, “

Obesity linked to improved survival in advanced prostate cancer.

Despite this “obesity paradox,” doctors do not recommend gaining weight with hopes of improving cancer outcomes.

Jason M Broderick

Padcev Plus Keytruda Reduces Risk of Death, Disease Progression in Advanced Bladder Cancer

Welireg Plus Lenvima Has ‘Promising Antitumor Activity’ in Kidney Cancer Subset

Drug Duo Sparks Encouraging Outcomes in Treatment of Clear Cell Kidney Cancer

Obese Patients Tend to Have Better Prostate Cancer Outcomes

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