Jordyn Sava 

Patients with advanced or metastatic clear cell renal cell carcinoma (RCC) treated with Welireg (belzutifan) tended to live longer before disease progression and had improved quality of life compared to those treated with Afinitor (everolimus), according to findings from the LITESPARK-005 trial that were presented at the 2024 

A total of 366 participating patients were randomly assigned to receive Welireg, a first-in-class HIF-2 alpha inhibitor, and 354 patients were randomized to receive Afinitor in the randomized, open-label, phase 3 study and were included in the patient-reported outcomes (PRO) analysis population. Both the Welireg and Afinitor groups had high completion rates for the Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index – Disease Related Symptoms (FKSI-DRS) and QLQ-C30 — both tools used to measure patient functioning and quality of life — at more than 90% at baseline and more than 55% at week 17.

Patients with advanced or metastatic clear cell renal cell carcinoma (kidney cancer) treated with Welireg in the LITESPARK-005 trial tended to experience longer time to disease progression and improved quality of life compared to those treated with Afinitor.

The trial included 366 patients receiving Welireg and 354 patients receiving Afinitor, with high completion rates for patient-reported outcomes assessments in both groups.

The study suggests that Welireg, which was approved in December 2023, may offer better disease-specific symptoms and quality of life for patients compared to Afinitor, supporting its use in heavily pretreated patients with advanced clear cell renal cancer.

The median time to disease progression (TTD) with Welireg was not reached in FKSI-DRS, 19.35 months in QLQ-C30 global health status/quality of life (GHS/QoL), and 19.32 months in QLQ-C30 physical functioning (PF) compared with 11.99, 10.19 and 13.83 months with Afinitor.

“These patient-reported outcomes indicate better disease-specific symptoms and quality-of-life associated with (Welireg) compared to (Afinitor). … These types of analyses might be more useful to patients than looking at these very specific graded (side effects),” said Dr. Thomas Powles, professor of genitourinary oncology at Queen Mary University of London; director, Barts Cancer Center, in a presentation of the data.

Prior LITESPARK-005 data established Welireg's efficacy in terms of progression-free survival (PFS; time from treatment until disease worsening or death) and overall response rate (ORR; percentage of patients whose disease shrinks or disappears from treatment) compared to Afinitor in advanced kidney cancer.

LITESPARK-005 randomized 746 patients with advanced RCC who progressed after treatment with anti-PD-1/PD-L1 and VEGF-targeted therapies to receive either Welireg 120 mg orally once daily or Afinitor 10 mg orally once daily. Thecoprimary end points of the trial were PFS and overall survival (OS; time from treatment until death of any cause).

Investigators also evaluated secondary end points including ORR, duration of response, the number of patients who experienced side effects, the number of patients who discontinued study treatment as a result of side effects, TTD of health-related QoL (HRQOL), TTD in PF, TTD in disease symptoms, change from baseline in HRQOL per the EORTC Core Quality of Life questionnaire C30 (EORTC QLQ-C30) items 29 and 30 score, change from baseline in physical functioning based on the EORTC QLQ-C30 items 1-5 score, change from baseline in disease symptoms according to the functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease Related Symptoms items 1-9 score and change from baseline in European Quality of Life 5 Dimensions per the 5-level Questionnaire Health Utility score.

Enrollment was open to patients with unresectable, locally advanced or metastatic disease who had received no more than three prior systemic agents for locally advanced or metastatic RCC and had adequate organ function.

 in December 2023 for the treatment of adult patients with advanced RCC whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor treatment.

“The randomized phase 3 trial was positive for progression-free survival and response. Indeed, (Welireg) now has FDA approval in pretreated patients, which is super exciting to have a new class of drug in our armory,” explained Powles.

This analysis presented at the 2024 Genitourinary Symposium delved into the PROs within the same trial. PROs were assessed using FKSI-DRS and EORTC QLQ-C30 questionnaires in all randomized patients who received at least one dose of the study treatment and completed at least one PROs assessment. Questionnaires were administered electronically on day 1 of weeks 1, 3, 5 and 9, every four weeks thereafter, at treatment discontinuation, and 30 days after the last dose.

“The FKSI-DRS stands for disease-related symptoms, so the questions we were asking focus on these symptoms with advanced cancer. They are not necessarily focused on side effects of drugs, whereas the EORTC QLQ-C30, that focuses more broadly actually on health-related and global quality-of-life,” Powles said.

With a median follow-up of 25.7 months at the data cutoff date at the second prespecified interim analysis of June 13, 2023, the median duration of treatment was 7.6 months with Welireg compared with 3.9 months with Afinitor. A total of 84 (22.6%) and 18 (5%) patients remained on treatment across the two arms.

“The good news is, over 90% of patients filled out the baseline questionnaire, and then 60% at week 17. As time goes by, it is harder and harder to get patients to continue to complete these questionnaires,” explained Powles.

Although side effects in the two arms were similar, the pattern of side effects was different, including more patients reporting cough with Afinitor vs Welireg (20.6% versus 8.3%), rash (18.9% versus 4.6%), stomatitis (37.8% versus 3.5%) and hyperglycemia (15.0% versus 2.7%). More patients treated with Welireg (308 patients; 82.8%) had any grade anemia compared with those given Afinitor (204 patients; 56.7%).

Overall, patients treated with Welireg experienced less severe disease-specific symptoms and a higher QoL compared with those receiving Afinitor, as measured by patient-reported outcome tools.

“Along with the improved progression-free survival and overall response rates, I think the findings I presented today further support the use of (Welireg) in heavily pretreated patients with advanced clear cell renal cancer,” concluded Powles.

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Welireg outperformed Afinitor in time to disease progression and patient-reported quality of life in the treatment of metastatic clear cell renal cell carcinoma. 

Welireg Delays Kidney Cancer Progression, Betters Quality of Life

Adding Adcetris (brentuximab vedotin) to frontline chemotherapy for patients with Hodgkin lymphoma led to improved outcomes, regardless of post-therapy PET scan results, which are typically used to predict outcomes, according to research presented at the 2023 School of Hematologic Oncology (SOHO) Annual Meeting.

Findings from the review showed that among the 40 patients treated with Adcetris plus doxorubicin, vinblastine and dacarbazine — a combination known as BvAVD — 24 were PET2 negative, meaning that the second PET scan detected cancer, and 12 were PET2 positive. All the patients who were PET2 negative had a negative end-of-treatment-PET, which indicated no progression of cancer. Of the 12 PET-positive patients, four had a positive end-of-treatment PET.

No meaningful impact on the management of patients was noted with the results of PET2 scans, and only one patient had a change in chemotherapy regimen after PET2 among all 40 patients who started on the BvAVD regimen initially. Additionally, no differences were observed in outcomes between the patients who were PET2 positive with a negative end-of-treatment-PET vs PET2-negative patients.

“We concluded that incorporation of (Adcetris) into frontline treatment results in superior efficacy, regardless of PET2 results. Our data, along with previous studies, points to the loss of predictive value, and therefore, redundancy of an interim PET2 scan, providing the evidence for safe omission of PET2 in treatment regimens containing (Adcetris),” Dr. Ravand Samaeekia, chief resident at Loma Linda University Internal Medicine, said during the presentation.

The standard-of-care for patients with Hodgkin lymphoma is interim PET2 due to its prognostic value and utility in PET-adapted treatment protocols. However, with the incorporation of Adcetris, a novel, anti-CD30 antibody-drug conjugate, into frontline treatment, the value of PET2 imaging is uncertain.

Investigators sought to determine whether interim PET assessment after two cycles of treatment still has predictive value for patients with Hodgkin lymphoma by reviewing frontline trials incorporating Adcetris and reported interim PET data. These trials were evaluated for three years, between December 2018-December 2022, and patients were from Loma Linda University Cancer Center. PET2 and end-of-treatment PET results of patients with Hodgkin lymphoma treated with BvAVD in the same period were also reviewed.

In three studies which have already been performed, ECHELON-1, AHOD1331 and BREACH, Adcetris was incorporated into the frontline and interim PET data were assessed. Each of these studies showed that progression-free survival or overall survival rates were significantly higher with Adcetris among patients with PET2-negative or PET2-positive disease.

In the ACCRU-LY study, which examined Adcetris with Opdivo (nivolumab) as a frontline treatment for patients with Hodgkin lymphoma, preliminary data showed a 97% rate of interim PET negativity with a 100% PFS rate at two years. The combination, which eliminated chemotherapy, was also well tolerated; however, some neuropathy concerns were noted.Although this trial did not meet its prespecified activity criteria, as the overall response rate noted was 61% instead of 80%, the combination was active in older patients.

“All these clinical trials are supporting the idea that receiving Adcetris has benefits, regardless of being a PET-positive or PET-negative patient,” said Samaeekia.

In the review presented at SOHO 2023, 40 patients were included and treated with BvAVD. A total of 24 were PET2-negative, and 12 were PET2-positive. Nineteen (48%) patients were male, and the median age was 22 years (range, 11-83). At initial diagnosis, 11 patients (28%) had Ann Arbor Stage 2 disease, 15 (37%) had stage 3 and 14 (35%) had stage 4 disease. Nineteen percent of patients had a low (0-2) International Prognostic Score while 21% had a high score (3-7), and the majority of patients (68%) had an ECOG performance status of 0-1, meaning that they could independently perform all or most of their daily activities.

All 24 patients with PET2-negative disease and eight patients with PET2-positive disease with a negative end-of-treatment PET remained in complete remission at the end of treatment.

While PET scans have been used to predict Hodgkin lymphoma outcomes, adding Adcetris to frontline therapy improved outcomes for patients, regardless of their results. 

Adcetris Improves Lymphoma Outcomes, Regardless of PET Scan Results

Patients with advanced hepatocellular carcinoma (HCC) whose disease progressed on immunotherapy may derive a survival benefit when treated with second-line Lenvima (lenvatinib), findings from a recent analysis demonstrated.

In particular, from the time that Lenvima was given to patients, the median progression-free survival (the time when a patient lives with cancer without worsening) was 3.7 months and median overall survival (the time when a patient with cancer is still alive) was 12.8 months. These results, which were presented at the 

, are comparable with survival findings from other studies using Lenvima as first-line therapy (initial treatment).

However, investigators, including Dr. Jennifer Gile, a hematology/oncology fellow at the Mayo Clinic in Rochester, Minnesota, looked to determine the optimal sequencing therapy for patients following progression on immunotherapy. As a result, an analysis was created to evaluate this in patients with advanced HCC who were diagnosed between 2010 and 2021.

The primary goals that were assessed in this trial were overall survival and progression-free survival.

Investigators identified 53 patients (median age, 67 years; 83% men) with advanced HCC who were treated with Lenvima following immunotherapy. Lenvima was given to 85% of patients in the second-line setting (treatment given when the initial treatment did not work or stopped working) and to 15% of patients in the third-line setting (when the initial treatment and subsequent treatment doesn’t work or stops working) or later. Of note, 72% of patients had died when researchers extracted these data.

Regarding safety, the most common side effects of any grade were fatigue (53%), high blood pressure (37%), aspartate aminotransferase (AST) elevation (a sign of liver or heart damage, cancer or other diseases; 30%), anorexia (28%), bilirubin elevation (the substance that forms when red blood cells break down that may result in jaundice; 25%) and diarrhea (25%).

Forty percent of patients reported severe or worse side effects. These included high blood pressure (25%), confusion (6%), acute kidney injury (2%), high levels of potassium in the blood (2%), alanine aminotransferase elevation (potentially indicating liver damage; 2%), proteinuria (high levels of protein in urine; 2%), joint pain (2%), heart failure (2%), AST elevation (2%), bilirubin elevation (2%), pain and swelling of the hands or feet (2%), sores in the mouth (2%), weight loss (2%), underactive thyroid (2%), anorexia (2%), fatigue (2%) and diarrhea (2%).

Additionally, treatment was stopped due to side effects in seven patients, including fatigue in two patients, confusion in two patients and heart failure, high blood pressure and elevated bilirubin in one patient each.

Lenvima is a multikinase inhibitor that gained approval by the Food and Drug Administration in the first-line setting for patients with advanced HCC. However, Tecentriq (atezolizumab) and Avastin (bevacizumab) are considered new standards of care as first-line therapy based on 

In the IMBrave150 trial, the combination of Tecentriq and Avastin led to statistically significant and clinically meaningful improvements in overall survival and progression-free survival compared with Nexavar (sorafenib).

A total of 501 patients were followed for a median of 15.6 months. The median overall survival seen was 19.2 months with the combination versus 13.4 months with Nexavar, and the median progression-free survival was 6.8 months versus 4.3 months, respectively. Treatment with Tecentriq plus Avastin also led to an improved confirmed objective response rate versus Nexavar at 27.3% versus 11.9 % with Nexavar. In the combination arm, ongoing responses were seen in 86.5% compared with 68.4% of the Nexavar arm.

Patients with advanced HCC who progressed after treatment with immunotherapy may have a survival benefit when treated with second-line Lenvima. 

Lenvima May Prolong Survival in Advanced Liver Cancer That Progressed on Immunotherapy

The two-drug combination of Keytruda (pembrolizumab) plus Lenvima (lenvatinib) was associated with prolonged benefit and safety in patients with malignant pleural mesothelioma, according to findings from the phase 2 PEMMELA clinical trial presented at the 2022 World Conference on Lung Cancer.

Preliminary results indicated the objective response rate — which is the percentage of patients whose disease shrunk — was 58%. According to the investigators, 76% of patients required dose reductions.

“This study met its primary end point, showing promising clinical activity of (Keytruda) plus (Lenvima) in patients with recurrent (malignant pleural mesothelioma) who progressed after chemotherapy, with remarkable but no unexpected toxicity,” said Li-Anne Douma, a doctoral candidate at The Netherlands Cancer Institute in Amsterdam who presented the results.

In patients with malignant pleural mesothelioma, there is a large unmet need for effective second-line treatment options. The PD-1 blocker, Keytruda, has shown a response rate up to 20% as monotherapy, whereas Lenvima, a multi-targeted tyrosine kinase inhibitor has synergistic interactions with PD-1 blocking in other tumors.

Because of this, investigators sought to evaluate the clinical activity and toxicity of the two agents in combination as treatment for patients with recurrent malignant pleural mesothelioma in the phase 2 single-arm, open-label, study.

The trial included 38 eligible patients with malignant pleural mesothelioma whose disease progressed after chemotherapy. They received intravenous Keytruda given at a dose of 200 milligrams (mg) once every three weeks plus Lenvima at 20 mg orally once a day.

Enrollment was open to patients aged 18 years or older with malignant pleural mesothelioma. Patients had an ECOG performance status of 0-1 (indicating that their disease had little to no effect on performing daily activities); measurable disease according to the modified RECIST version 1.1, a system of measuring mesothelioma; and had received prior chemotherapy. Those enrolled remained on treatment for up to two years, until unacceptable toxicity, or disease progression evaluated by CT-scan every six weeks.

Objective response rate was defined as the proportion of patients with complete response (complete disappearance of disease), or partial response (shrinking of disease), with secondary end points including safety of the treatment combination, disease control rate at months three and six and progression-free survival (time from treatment until disease gets worse).

At a data cutoff of March 31, 2022, 22 of the 38 patients had reached partial response as best overall response, and 15 of these patients had confirmed partial response of 39.5%. Among the seven patients who had unconfirmed partial response, three can still reach confirmed partial response.

In regard to safety, most of the side effects were deemed mild or moderate and consisted of fatigue (21 patients), hoarseness (21 patients), anorexia (13 patients), diarrhea (13 patients), high blood pressure (five patients) and elevated alanine aminotransferase/ aspartate transaminase levels, which could be an indicator of liver damage (five patients).

Serious or severe treatment-related side effects were observed in 26 patients with the most common serious side effects being high blood pressure in eight patients (24%) and anorexia in three (18%). Additionally, there were two patients with severe myositis (inflamed muscles) as well as 10 patients with 13 treatment-related serious side effects.

Dose reductions or permanent discontinuation of Lenvima treatment were required by 76% of all patients due to toxicity concerns. For Keytruda, two of the 38 patients (8%) had permanent discontinuation on the trial.

Patients with malignant pleural mesothelioma tended to have prolonged benefit when treated with Keytruda plus Lenvima in the PEMMELA clinical trial. 

Jordyn Sava

Welireg Delays Kidney Cancer Progression, Betters Quality of Life

Adcetris Improves Lymphoma Outcomes, Regardless of PET Scan Results

Lenvima May Prolong Survival in Advanced Liver Cancer That Progressed on Immunotherapy

Majority of Patients with Mesothelioma Subtype Responded to Keytruda-Lenvima Combo

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