Jordyn Sava 

Long-term benefits were improved in some patients with advanced non-small cell lung cancer (NSCLC) enrolled in experimental combination groups, although none of the groups met the study’s desired result, according to data presented at the 

Of these combinations, Imfinzi (durvalumab) plus monalizumab and Imfinzi plus ceralasertib were the stand-out treatments in terms of benefit, according to Dr. Pascale Tomasini, an associate professor of thoracic oncology in the Multidisciplinary Oncology and Therapeutic Innovations Department of the Cancer Research Center in Marseille, France.

Although the trial didn't meet its primary endpoint, some patients with advanced NSCLC experienced promising long-term benefits from the Imfinzi plus monalizumab and Imfinzi plus ceralasertib combinations.

Although the primary goal of 12-week disease control rate (DCR) wasn't met, some patients experienced disease control and responses, indicating potential benefits.

The combinations were generally well-tolerated, suggesting that these treatments might be suitable for many patients.

The results of the PIONeeR trial highlight the ongoing importance of research to develop new and effective treatments for NSCLC and other cancers.

In a live presentation, Tomasini explained that the PIONeeR trial “used an innovative and adaptive design to identify signal of efficacy of new types of immunotherapy combinations.”

To explore new ways to overcome PD-(L)1 inhibitor resistance, 114 patients with advanced NSCLC were randomly assigned to one of four experimental groups or a control group. Patients on group A received Imfinzi plus monalizumab (28 patients), group B received Imfinzi plus oleclumab (MEDI9447; three patients), group C received Imfinzi plus ceralasertib (32 patients), group E received Imfinzi plus Orpathys (savolitinib; 20 patients), and the control group, group D, received Taxotere (docetaxel) (31 patients).

For this trial, the primary goal was the 12-week disease control rate (DCR; the proportion of a population that is protected against a specific disease), and secondary goals included objective response rate (ORR; the percentage of people whose disease shrinks or disappears after treatment), overall survival (OS; the time from the start of treatment when a patient with cancer is still alive), progression-free survival (PFS; how long a person lives without their disease getting worse), duration of response (DOR; the length of time a person's disease remains in remission after treatment) and safety and tolerability. The adaptive design of the trial was to let investigators stop groups quickly when there was a lack of efficacy and open new combination groups when data emerged.

The mean estimated 12-week DCR was 24.1% in group A, 50% in group C, 13.6% in group E, and 54.5% in the control group. The ORR, consisting of all partial responses, was 17.9% (five patients) in group C and 25% (five patients) in the control group in the evaluable population. In the total intention-to-treat population, the ORR was 15.6% in group C and 16.1% in the control group, respectively. Stable disease was observed in 42.9% of patients in group A, 66.7% in group B, 57.1% in group C, 30% in group E, and 50% in the control group.

“In the control [group] with [Taxotere], 31 patients were enrolled, but only 23 were treated mainly due to consent withdrawal,” Tomasini said. “Two [groups] had to be closed prematurely during the trial. [Group] B with the oleclumab was closed after only three patients enrolled because of lack of efficacy shown in a concomitant trial, the HUDSON study. In [group] E with Orpathys was closed after 20 patients enrolled because of lack of efficacy shown in the first interim analysis of the PIONeeR trial.”

The secondary goals of PFS and OS were available for groups A, C, E, and the control group. The median PFS was 1.6 months in group A, 4.1 months in group C, 1.4 months in group E, and 4.4 months in the control group. In these respective groups, the median OS was 11.7 months, 17.4 months, 7.1 months, and 13.8 months, although group C’s median OS was biased based on length of follow-up.

In terms of safety, treatment-related side effects were observed in 82.1% of group A, 100% of group B, 93.5% of group C, 95% of group E and 100% of the control group. Grade 3 (severe) or worse side effects related to treatment occurred in 7.1% of patients in group A, 33.3% in group B, 54.8% in group C, 30% in group E, and 43.5% in the control group. There was one treatment-related death, which occurred in group C.

There were three treatment interruptions and two discontinuations in group A, one each in group B, 10 interruptions and eight discontinuations in group C, nine interruptions and seven discontinuations in group E, and six each in the control group.

All the patients enrolled on PIONeeR had disease progression after more the six weeks of anti–PD-(L)1 therapy in the second or third line or more than 12 weeks of anti–PD-(L)1 plus platinum-based chemotherapy, and ECOG performance status of 0 or 1. Patients were stratified by center, squamous vs non-squamous histology, and progression on prior treatment before or after 24 weeks.

In the intention-to-treat population, the median age was 63 years, most patients were male (61.4%), 53.5% had ECOG performance status of 1 (meaning patients were able to complete most daily tasks independently), and 46.5% had a status of 0 (completing daily tasks entirely independently). A small number of patients had liver (10.5%) or brain (7.9%) metastases. Sixty-six percent of patients experienced disease worsening or spreading on a prior line of therapy for more than 24 weeks before enrollment.

“In conclusion, the PIONeeR trial is an academic collaborative success in exploring how to overcome resistance to PD-1 and PD-L1 inhibitors in advanced NSCLC,” Tomasini said. “[While] no experimental group formally met the efficacy target, we observed that some patients derived a long-term clinical benefit from some combinations, especially including ceralasertib and monalizumab and comprehensive biomarker analysis are ongoing to be able to predict among the patients who are likely to have this long-term clinical benefit.”

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Articles

Imfinzi with monalizumab and ceralasertib showed promising long-term benefits in advanced NSCLC, but no other combinations significantly improved results.

Adaptive NSCLC Study Fails to Produce Improved Results, Clinical Benefits in Some

Rytelo is recommended for patients with lower-risk myelodysplastic syndromes (MDS) who experience anemia. 

The National Comprehensive Cancer Network (NCCN) now recommends Rytelo (imetelstat) as a treatment for patients with lower-risk myelodysplastic syndrome (MDS) who have symptomatic anemia.

The NCCN is comprised of leading oncology centers. They publish treatment guidelines to guide cancer care that are based on the latest clinical evidence. The organization now states that Rytelo is a Category 1 and Category 2A therapy for this patient population.

Treatments are designated as Category 1 and 2A when there is a strong NCCN consensus, with at least 85% agreement, that the intervention is appropriate.

 in June 2024 for the treatment of adult patients with low- to intermediate-1 risk MDS with transfusion-dependent anemia who require at least four red blood cell units over eight weeks and for those who have not responded to, have lost response to, or are ineligible for erythropoietic stimulating agents (ESAs; medications used to stimulate the bone marrow to produce more red blood cells).

The approval was based on data from the phase 3 IMerge trial which was published in 

 in December 2023 and supports the NCCN’s updated guidelines.

“We believe that the placement of Rytelo in the updated MDS NCCN Guidelines reflects the strength of our phase 3 data and the US Prescribing Information and that these updates will help to increase awareness and uptake of Rytelo as a compelling new treatment option for these patients,” Dr. Faye Feller, Geron’s executive vice president and chief medical officer, said in a press release.“We are encouraged by the increasing dialogue across hematologists rethinking treatment approaches and sequencing given the availability of Rytelo for eligible lower-risk MDS patients with transfusion-dependent anemia.”

Rytelo works by inhibiting telomerase enzymatic activity (which is associated with cell production) and is the first and only telomerase inhibitor approved by the FDA.

The IMerge trial was a randomized, multicenter, phase 2/3 trial that enrolled patients aged 18 years and older with MDS and an ECOG performance status of 0, 1 or 2, indicating that they can perform — at the very least — all of their self-care activities. Patients were randomly assigned to 1 of 2 arms: Two-thirds of the patients received Rytelo while the other third received a placebo (inactive drug).

The primary end point for parts 1 and 2 of the trial evaluated the percentage of patients without any red blood cell transfusion during any consecutive eight-week period. Secondary end points included assessing side effects, duration of red blood cell transfusion independence, time to eight-week red blood cell transfusion independence, percentage of patients with hematologic improvement, percentage of patients with complete or partial remission, overall survival, progression-free survival, time to progression to acute myeloid leukemia, amount of red blood cell transfusions, relative change in red blood cell transfusions, percentage of patients receiving any myeloid growth factors and how the body interacts with the drug.

IMerge met its primary and key secondary end points as patients enrolled and treated with Rytelo had significantly higher rates of red blood cell transfusion independence (39.8%) versus those treated with placebo for at least eight consecutive weeks (15%). Rates of red blood cell transfusion independence for at least 24 weeks were 28% with Rytelo and 3.3% with placebo.

Red blood cell transfusion independence was also durable and sustained in the Rytelo-treated population, with a median duration of approximately one year for eight-week responders and 1.5 years for 24-week responders, respectively.

Safety findings showed that the most frequently seen side effects from Rytelo were laboratory abnormalities, including thrombocytopenia (decreased type of white blood cell called thrombocytes), decreased white blood cells, neutropenia, increased aspartate aminotransferase, increased alkaline phosphatase, increased alanine aminotransferase (increase in a protein that could indicate liver damage), fatigue, longer time to blood clot, pain, COVID-19 infections and headache.

“With [Rytelo], we have an option that comes between ESAs and [Reblozyl (luspatercept)], and something that I would consider to be more traditional chemotherapy like a hypomethylating agent,” said Dr. Mikkael A. Sekeres, in an interview with CURE®’s sister publication, Targeted Oncology.

The National Comprehensive Cancer Network now recommends Rytelo for patients with myelodysplastic syndrome who require blood transfusions. 

NCCN Recommends Rytelo for Anemia in Patients With MDS 

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.

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. 

Jordyn Sava

Adaptive NSCLC Study Fails to Produce Improved Results, Clinical Benefits in Some

NCCN Recommends Rytelo for Anemia in Patients With MDS

Welireg Delays Kidney Cancer Progression, Betters Quality of Life

Adcetris Improves Lymphoma Outcomes, Regardless of PET Scan Results

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