Benjamin P. Saylor

The treatment combination of Welireg (belzutifan) and Cabometyx (cabozantinib) demonstrated durable anti-tumor activity in patients with clear cell renal cell carcinoma (ccRCC) who were treatment-naïve or had previous treatment with immunotherapy, according to results from a phase 2 trial.

The data from the phase 2 trial, LITESPARK-003, were presented at the 

2023 European Society for Medical Oncology (ESMO) Annual Congress

 in Madrid, Spain by Dr. Toni K. Choueiri, professor of medicine at Harvard Medical School and an attending physician, director of the Genitourinary Oncology Disease Center, and director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts.

In his presentation, Choueiri explained that the inactivation of the von Hippel-Lindau gene (VHL; a mutated gene that increases the growth of abnormal cells) results in the overexpression of hypoxia-inducible factors (HIFs; proteins responsible for cell responses to changes in oxygen levels and activate specific genes for cell growth and survival).

Choueiri added that initial results from LITESPARK-003 showed promising anti-tumor activity in patients who were either treatment naïve (cohort 1) or previously treated with immunotherapy (cohort 2).

Cohort 1 had 50 patients enrolled and treated, with a median follow-up of 24.3 months; however, 24 patients discontinued treatment. Cohort 2 had 52 patients enrolled and treated, with a median follow-up of 39.8 months. Forty-six patients discontinued treatment.

At a median follow-up of 14 months, there was a 57% overall response rate (ORR; percentage of patients who had a partial or complete response to treatment) in cohort 1. At a median follow-up of 24.6 months, there was a 31% ORR in cohort 2. At the 2023 ESMO Congress, Choueiri presented updated findings from both cohorts.

In cohort 1, 28 patients (56%) were International Metastatic RCC Database Consortium (IMDC) favorable risk, and 22 patients (44%) were IMDC intermediate/poor risk. In cohort 2, 11 patients (21%) were IMDC favorable risk and 41 patients (79%) were IMDC intermediate/poor risk.

Choueiri reported that ORR in cohort 1 was 70% in the entire cohort, 79% in patients who were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable risk and 59% in patients who were IMDC intermediate/poor risk.

In cohort 2, ORR was 31% in the entire cohort, and 27% in patients who were IMDC favorable risk and 32% in patients who were IMDC intermediate/poor risk.

Choueiri reported that all patients in cohort 1 had a reduction in target lesion size and that in cohort 2, 45 of 51 patients (88%) with available post-baseline imaging saw a reduction in target lesion size.

In cohort 1, the median progression-free survival (PFS; time during and after treatment when the patient lives and the cancer does not worsen) was 30.3 months, and in cohort 2, the median PFS was 13.8 months. In cohort 1, the median overall survival (OS; length of time from diagnosis or start of treatment when a patient still lives) was not reached (meaning more than half of the patients in that cohort had not died) and in cohort 2, the median PFS was 26.7 months.

Any-grade treatment-related side effects were reported in 100% of cohort 1 and 98% of cohort 2. Treatment-related side effects of grade 3 or higher (mild to severe) occurred in 23 patients (46%) in cohort 1 and 33 patients (64%) in cohort 2.

There were no treatment-related deaths in cohort 1, but one patient experienced treatment-related death in cohort 2. Seven patients (14%) in cohort 1 discontinued any drug because of treatment-related side effects, and 11 patients (21%) in cohort 2 discontinued any drug because of treatment-related side effects.

Serious treatment-related side effects were observed in seven patients (14%) in cohort 1 and 16 patients (31%) in cohort 2, with dose reduction because a treatment-related side effect occurred in 38 patients (76%) and 37 patients (71%) in cohorts 1 and 2, respectively.

“(Welireg) plus (Cabometyx) continue to show durable anti-tumor activity in patients with clear cell RCC who are treatment-naïve or previously treated,” Choueiri concluded.

For more news on cancer updates, research and education, don’t forget to 

Articles

The Welireg-Cabometyx treatment combination demonstrated anti-tumor activity for some patients with clear cell renal carcinoma, according to a phase 2 trial.


Welireg Plus Cabometyx Shows Anti-Tumor Activity in Kidney Cancer Type

Pluvicto improved progression-free survival in certain patients with prostate cancer, recent research showed. 

Treatment with Pluvicto (177-Lu-PSMA-617) improved the duration of time when a patient’s disease did not progress with a favorable safety profile in patients with metastatic castration-resistant prostate cancer (mCRPC) who were taxane-naïve, according to recent results from a phase 3 trial.

Findings from the PSMAfore trial were presented at the 2023 

European Society for Medical Oncology Annual Congress

 in Madrid, Spain, by Dr. A. Oliver Sartor, a professor of medicine, urology and radiology at Mayo Clinic in Rochester, Minnesota.

Eligibility criteria included diagnosis of mCRPC, candidacy for androgen receptor pathway inhibitor (ARPI) change following one progression on prior ARPI treatment and having at least one PSMA-positive and no exclusionary PSMA-negative lesions. Of note, ARPIs are substances that keep prostate cancer cells from growing.

Patients were randomly assigned to Pluvicto or ARPI change (Zytiga [abiraterone]/Xtandi [enzalutamide]).

“Very, very importantly, those people on the hormonal therapies were able to crossover and to receive the lutetium if they in fact had met the (radiographic progression-free survival) end point,” Sartor said.

The study’s primary endpoint was progression-free survival (the length of time when a patient with cancer is alive without disease worsening), and the key secondary endpoint was overall survival (the time from the start of treatment when a patient with cancer is still alive).

A total of 234 patients each received either Pluvicto or ARPI change. Fifty-one patients (21.8%) in the Pluvicto arm discontinued treatment due to radiographic progression versus 146 patients (62.4%) in the ARPI change arm. Of the latter group, 123 patients (84.2%) crossed over to receive treatment with Pluvicto.

Baseline characteristics were similar between the Pluvicto and ARPI change groups. In the Pluvicto group, 119 patients (50.9%) had previously received Zytiga, and 94 patients (40.2%) had previously received Xtandi, whereas in the ARPI change group, 130 patients had previously received Zytiga (55.6%) and 84 patients (35.9%) had previously received Xtandi.

Sartor reported that the primary endpoint of progression-free survival was met, meaning that the results of the trial were similar of the expectations of the researchers before work started on the trial.

“No doubt about it, this is unequivocally a positive trial by the (radiographic progression-free survival) criteria. Quite positive,” Sartor commented.

Median progression-free survival was 12.02 months in the Pluvicto group versus 5.59 months in the ARPI change group.

Looking at radiographic response rates in measurable disease, objective response rate (the percentage of patients with a partial or complete response to treatment) was 50.7% in the Pluvicto group and 14.9% in the ARPI change group. Specifically, there was a 21.1% complete response rate (the disappearance of all signs of cancer from treatment) in the Pluvicto group versus 2.7% in the ARPI change group. Median duration of response (the time from when a patient first responded to treatment until progression or death) was 13.63 months in the Pluvicto group versus 10.05 months in the ARPI change group.

Confirmed PSA decrease of at least 50% was seen in 57.6% of patients in the Pluvicto group compared with 20.4% of patients in the ARPI change arm.

At a median follow-up of 12.72 months, median overall survival was 19.25 months in the Pluvicto group and at a median follow-up of 13.08 months, median overall survival was 19.55 months in the ARPI change group.

Regarding side effects, 77 severe or life-threatening side effects were observed (33.9%) in the Pluvicto group versus 100 (43.1%) in the ARPI change group. Forty-six serious side effects (20.3%) occurred in the Pluvicto group versus 65 (28.0%) in the ARPI change group. There were eight side effects leading to dose adjustment (3.5%) in the Pluvicto group versus 35 in the ARPI change group. Side effects occurring in at least 10% of patients in either arm included dry mouth, weakness, nausea, anemia, fatigue, constipation, decreased appetite, joint pain, COVID-19, diarrhea, back pain, vomiting, leg swelling and weight loss.

“In summary, PSMAfore met the primary (radiographic progression-free survival) end point with a very favorable adverse event profile, in taxane-naive patients with metastatic CRPC,” Sartor said.

Patients with metastatic castration-resistant prostate cancer who were never treated with a taxane derived a progression-free survival benefit from treatment with Pluvicto.

Pluvicto Improves Survival Without Progression in Certain Patients With Prostate Cancer

More than half of patients with metastatic castration-resistant prostate cancer treated with the radioligand therapy 177Lu-PSMA-I&T experienced decreases in prostate-specific antigen (PSA) levels of at least 30%, according to recent study findings.

Findings from this study were presented at the 2023 American Urological Association Annual Meeting in Chicago.

“PSMA-targeted radioligand therapy with lutetium PSMA-617 Is associated with prolonged overall survival in patients with metastatic castration-resistant prostate cancer, but data regarding the oncological efficacy and toxicity of lutetium PSMA-I&T are limited,” explained study author Dr. Derya Tilki, visiting faculty at Koç University in Istanbul, Turkey, and urologist at Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Germany.

For the study, a total of 33 patients with metastatic castration-resistant prostate cancer received a total of 88 cycles of 177Lu-PSMA-I&T.

Oncological outcomes measured included clinical progression-free survival, defined as the time from the first radioligand therapy cycle to any radiological or biological progression of the disease.

“We assessed response according to PSA changes and imaging response,” Tilki said.

The investigators also assessed side effects related to the treatment.

Median patient age at the time of first radioligand therapy cycle was 71.6 years. PSA response of any amount was seen in 22 patients (69%), at least 30% in 18 patients (56%), at least 50% in 11 patients (33%) and at least 90% in six patients (33%).

Clinical progression-free survival following the first cycle of radioligand therapy was 6.3 months, and overall survival following the first cycle was 21.4 months.

Regarding side effects, nephrotoxicity (what occurs when kidneys are damaged by a drug) was observed in four patients; this side effect was considered mild to moderate in two patients, moderate to severe in one patient and severe to life-threatening in one patient. Hematotoxicity (which can lead to bleeding, infection or anemia) was experienced by six patients (18.2%). The investigators also reported six patients with some degree of myelotoxicity (affecting the bone marrow).

Limitations of the study included its retrospective nature as well as the varying histories of the patients included in the study, according to Tilki.

“These are one of the few data for PSMA radioligand therapy with PSMA-I&T in contrast with PSMA-617, and the toxicity profile is very similar (to that of) PSMA-617,” Tilki said in her presentation of the data.

Patients with metastatic castration-resistant prostate cancer treated with radioligand therapy, a form of targeted therapy, had improvements in PSA levels and survival with favorable side effect profiles. 

PSMA-Targeted Therapy May Decrease PSA Levels in Metastatic Prostate Cancer Subset

Post-chemotherapy Cabometyx (cabozantinib) is a tolerable treatment option for patients with advanced urothelial carcinoma (bladder cancer), though the drug did not have a significant benefit compared to placebo in the phase 2 ATLANTIS clinical trial.

Findings from the trial were presented by first author Robert J. Jones, at the 

2022 American Society of Clinical Oncology Annual Meeting

The ATLANTIS trial included patients with advanced urothelial carcinoma who underwent four to eight cycles of first-line chemotherapy, during which time they were prescreened for tissue-based biomarkers. Patients with ongoing clinical benefit after chemotherapy were offered randomization into one of several substudies based on biomarker status. Patients with a DNA repair deficiency were randomized to Rubraca (rucaparib) compared to placebo, patients who were androgen receptor biomarker-positive were randomized to Xtandi (enzalutamide) compared to placebo, and patients who were “all biomarkers negative” received Cabometyx or placebo.

Patients in the Cabometyx arm received 40 mg once daily vs matching placebo. The main goal of the study was progression-free survival (time from treatment until disease worsens). Secondary end points included overall survival (time from treatment until death of any cause), confirmed response rates and safety and tolerability.

Recruitment was discontinued after 61 patients were randomized due to a United Kingdom-wide recruitment hiatus beginning in March 2020 because of the COVID-19 pandemic, and also due to the presentation of data in June 2020 supporting the use of Bavencio (avelumab) in the maintenance setting.

Jones reported an average progression-free survival of 13.7 weeks with Cabometyx, compared to 15.8 weeks with placebo. Average overall survival was 75.5 weeks with Cabometyx, compared to 82.9 weeks with placebo.

Median duration of treatment was 13 cycles for Cabometyx compared to 10 cycles for placebo. Overall response rate (percentage of patients whose disease shrunk as a result of treatment) was 3.3% for Cabometyx and 6.5% for placebo.

Regarding safety, side effects seen more commonly in patients receiving Cabometyx and placebo included fatigue (56.7% and 32.2%, respectively), hypertension (43.3% and 12.9%), nausea (30% and 19.4%) and diarrhea (40.0% vs 6.5%).

“Notably, 43% of patients receiving (Cabometyx) had to reduce the dose from 40 to 20 mg, although there were no treatment discontinuations due to toxicity,” said Jones, professor of clinical research at the University of Glasgow Institute of Cancer Sciences in Glasgow, Scotland.

In his concluding remarks, Jones said, “Though underpowered, this study does not support further investigation of cabozantinib alone as a maintenance therapy after platinum-based chemotherapy in unselected patients with advanced urothelial cancer.”

Jones added that negative patient selection for DNA repair deficiency and androgen receptor biomarkers may have biased interpretation of the findings.

“Future trials should consider combining novel agents with maintenance immunotherapy,” Jones said.

While Cabometyx had a favorable side effect profile, it did not lead to a significant survival advantage over placebo in a clinical trial. 

Benjamin P. Saylor

Welireg Plus Cabometyx Shows Anti-Tumor Activity in Kidney Cancer Type

Pluvicto Improves Survival Without Progression in Certain Patients With Prostate Cancer

PSMA-Targeted Therapy May Decrease PSA Levels in Metastatic Prostate Cancer Subset

Cabometyx Failed to Improve Survival in Advanced Bladder Cancer

Latest News