Tony Berberabe, M.P.H.

Real-world data compared treatment with three CDK4/6 inhibitors in HR-positive, HER2-negative metastatic breast cancer. 

When comparing three CDK4/6 inhibitor combinations during the initial treatment for hormone receptor (HR)-positive, HER2-negative metastatic (spreading) breast cancer, no significant overall survival (OS) advantage was found, as presented during the 

2024 San Antonio Breast Cancer Symposium (SABCS)

“To date, we have no head-to-head phase 3 studies comparing the CDK4/6 inhibitors,” noted Dr. Kari B. Wisinski, professor of medicine at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin, in a presentation of the data.

The median follow-up was 33 months for the Ibrance (palbociclib) plus an aromatase inhibitor (AI; 6,831 patients) group, 16 months for the Kisqali (ribociclib) plus AI (1,279 patients) group and 21 months for the Verzenio (abemaciclib) plus AI (1,036 patients) group.

Overall survival (OS): time from diagnosis or treatment start until death from any cause.

Progression-free survival (PFS): time during which the disease does not worsen.

Neutropenia: low levels of neutrophils, a type of white blood cell.

Thrombocytopenia: low levels of platelets in the blood, which may cause easy bruising or bleeding.

Primary end point: the main objective measured at the end of the study to see if treatment worked.

Real-world data was used from a retrospective study analyzing 9,146 patients from 280 US sites. The study investigators compared OS rates between treatment groups.

The median OS before an unadjusted analysis in the Ibrance plus AI group was 54.4 months, 60.3 months in the Kisqali plus AI group and not reached (NR) in the Verzenio plus AI group. When an OS is not reached, it means not enough patients in the respective group died at the time of data collection. The OS rates in the Ibrance plus AI group at 12, 24 and 30 months were 89.6%, 77.4% and 71.4%, respectively. For the Kisqali plus AI group, these OS rates were 90%, 78% and 73.3%. In the Verzenio plus AI group, the OS rates were at 12, 24 and 30 months were 88.4%, 76.1% and 71.5%.

After applying the adjusted analysis, the median OS for the Ibrance plus AI group was 54.6, 59 months for the Kisqali plus AI group and 64.5 months for the Verzenio plus AI group. The OS rates at 12, 24 and 30 months for the Ibrance plus AI group were 89.7%, 77.5% and 71.4%, respectively. These were 89.2%, 77.3% and 72.2% for the Kisqali plus AI group, respectively. For the Verzenio plus AI group, the OS rates were 88.2%, 76.1% and 71.5%, respectively.

Also in the adjusted analysis, 3,714 deaths were reported across all three groups: 3,096 in the Ibrance plus AI group (45.3%), 328 in the Kisqali plus AI group (25.6%) and 290 in the Verzenio plus AI group (28%). The median follow-up duration in group 1 was 33 months, 15.7 months in the Kisqali plus AI group and 21.5 months in the Verzenio plus AI group.

Regarding side effects, there were higher rates of neutropenia in the Ibrance plus AI group (67%) than the Kisqali plus AI group (60%) and the Verzenio plus AI group (21.9%). However, anemia was greater in the Ibrance plus AI group (5.4%) and the Verzenio plus AI group (6%) versus the Kisqali plus AI group (0.9%). Thrombocytopenia was consistent across the three groups: 1.6% for the Ibrance plus AI group, 0.9% for the Kisqali plus AI group and 1.9% for the Verzenio plus AI group.

“Now there are some limitations for this analysis. The [Ibrance plus AI] and [Verzenio plus AI] cohorts had smaller numbers and shorter follow-ups, and the point estimates were relatively (or possibly) unstable after 30 months. In addition, as always with real-world analysis, there is potential for unmeasured confounders,” Wisinski noted.

Wisinski applied these real-world data to the following phase 3 trials: PALOMA-2, MONALEESA-2, MONALEESA-3, MONALEESA-7 and MONARCH-3.

The primary end point for each study was progression-free survival (PFS), and all three demonstrated benefit, Wisinski explained. When comparing the median OS, Wisinski stated that “median OS has been improved with the addition of [Kisqali], [Verzenio] demonstrated a clinical meaningful benefit but it was not statistically significant, and [Ibrance] did not provide benefit.” In the real-world analysis the median OS rates were quite consistent with what was observed in these studies, Wisinski added.

Patients included in the trial had HR-positive, HER2-negative metastatic breast cancer, were 18 years or older and started index treatment with either Ibrance plus AI, Kisqali plus AI or Verzenio plus AI.

“The P-VERIFY study suggests that there is no difference in OS among first-line CDK4/6 inhibitors and this would align with the PFS data that we have from those first-line studies,” Wisinski concluded. “However, the statistically OS beneficent that we have seen as only been with [Kisqali]. I think that longer follow-up would be very valuable and although real-world analyses have limitations it is unlikely that we will have a head-to-head study, and thus, these data add to the information that we have.”

“Comparative Overall Survival of CDK4/6 Inhibitors Plus an Aromatase Inhibitor (AI) in HR+/HER2– MBC in the US Real-World Setting.” By Dr. Hope S. Rugo, et al. Presented at the San Antonio Breast Cancer Symposium, San Antonio, Abstract PS2-03.

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Articles

The comparison of three CDK4/6 inhibitor combinations for HR-positive, HER2-negative metastatic breast cancer revealed no significant overall survival (OS) advantage among them. Real-world data from 9,146 patients showed median OS rates of 54.6 months for Ibrance, 59 months for Kisqali, and 64.5 months for Verzenio. Side effects varied, with higher neutropenia in the Ibrance group. Limitations include smaller cohorts and potential confounders. The findings align with phase 3 trials, indicating no OS difference among first-line CDK4/6 inhibitors, except for Kisqali showing statistical OS benefit.

No significant survival benefits were found when comparing three CDK4/6 inhibitor combinations during initial treatment for HR-positive, HER2-negative metastatic breast cancer.

CDK4/6 Inhibitor Combos Miss Survival Goal in Metastatic Breast Cancer Subset

Treatment with Jaypirca was shown to reduce treatment discontinuations in patients with CLL or SLL. 

Among patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), Jaypirca (pirtobrutinib) demonstrated superior progression-free survival (PFS) and low rates of treatment discontinuation versus the investigator’s choice of treatment, according to findings from the prospective phase 3 BRUIN CLL-321 trial, presented at the 

In the study, patients with CLL or SLL were randomly assigned to receive Jaypirca monotherapy (119 patients) or Zydelig (idelalisib) plus Rituxan (rituximab) or bendamustine plus Rituxan (119 patients; IdelaR/BR). The primary end point was PFS and was met at the trial’s primary analysis in August 2023. The secondary end point was overall survival (OS) with a final analysis in August 2024.

At a median follow-up of 19.4 months, patients in the Jaypirca group had a median PFS of 14 months. At a median follow-up of 17.7 months, patients in the idelaR/BR group had a median PFS of 8.7 months. The independent review committee (IRC) reported that Jaypirca reduced the risk of progression or death by 46%.

Event-free survival (EFS): time until a patient experiences disease progression, death or a specific event.

Progression-free survival (PFS): time until a patient's disease worsens or death.

Overall survival (OS): time a patient lives after a diagnosis, regardless of disease status, until death by any cause.

The investigator-assessed PFS showed that at a median follow-up of 19.4 months, median PFS was 15.3 months in the treatment group versus 9.2 months in the control group at a median follow-up of 17.5 months. Jaypirca reduced the risk of progression or death by 52% in the investigator assessment.

“The investigator assessment of PFS was consistent with the independent review committee,” Dr. Jeff P. Sharman, director of research, Williamette Valley Cancer Institute, and medical director of hematology research at the US Oncology Network, in Eugene, Oregon, said during a presentation of the data at the meeting.

The safety profile for the Jaypirca was consistent with prior phase 1 and 2 trials. Treatment-related side effects led to discontinuation in 5.2% of patients who received Jaypirca versus 21.1% among patients who received IdelaR/BR treatment. When adjusting for exposure, the incidence rate of treatment-emergent side effects was lower with Jaypirca compared with IdelaR/BR.

Investigators also evaluated side effects of special interest (AESI) that are common to BTK inhibitors. Any-grade hypertension was reported in 6.9% of patients and grade 3 (severe) or worse was reported in 2.6% of patients. “Although patients with atrial arrhythmias were not excluded from the trial, cumulative event rates were low,” Sharman said. “Furthermore, two of the three subjects with treatment emergent atrial fibrillation had a prior history,” he continued.

Jaypirca was also favored in event-free survival (EFS). At a median follow-up of 19.4 months, the experimental group had a median EFS of 14.1 months versus 7.6 months in the control group at a median follow-up of 18.7 months. Jaypirca reduced the risk of an event by 61%.

“The event-free survival end point captures not only progression and death, but also discontinuations for toxicity, and thus better captures the integrated efficacy and safety of the intervention,” Sharman said.

The time to next treatment (TTNT) or death was also evaluated. At a median follow-up of 20 months, the experimental group demonstrated a median TTNT of 24 months versus 10.9 months in the control group at a median follow-up of 20.2 months. Jaypirca reduced the risk of starting next treatment or death by 63% with a median TTNT of about 24 months. “This captures the overall efficacy of the treatment as patients with IRC-determined asymptomatic radiographic progressions who are benefitting from therapy were not mandated to discontinue treatment,” Sharman said.

When TTNT was stratified by prior exposure to Venclexta (venetoclax), patients who received Jaypirca but were naïve to the BCL2 inhibitor (59 patients/group) had a median TTNT of 29.5 months versus 12.5 months for those who received IdelaR/BR. In patients who were previously treated with venetoclax (60 patients/group), the median TTNT was 20 months in the treatment group versus 8.7 months in the control group.

“[Jaypirca] was able to delay subsequent treatment or death for 2.5 years in patients who were naive to venetoclax, demonstrating that continued BTK inhibition can be an effective strategy after failure of first- or second-generation BTK agents,” Sharman said.

Although OS was evaluated, the study was not powered to detect the difference between the two groups, noted Sharman. Further, the analysis was confounded because 76% of patients were allowed to cross over post-progression.

PFS among clinical subgroups also demonstrated a consistent benefit in favor of Jaypirca and this was observed across molecular characteristics, including TP53 status, complex karyotype and IGHV status.

“[Jaypirca] is an effective, well-tolerated agent in patients with difficult-to-treat disease and provides a clinically meaningful way to sustain BTK inhibition,” Sharman concluded.

“BRUIN CLL-321: Randomized phase III trial of Jaypirca versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma” By Dr. Sharman JP, et al., 

Jaypirca (pirtobrutinib) demonstrated superior progression-free survival (PFS) and lower treatment discontinuation rates compared to standard treatments in patients with previously treated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 BRUIN CLL-321 trial showed Jaypirca reduced the risk of progression or death by 46% to 52% and had a favorable safety profile. Event-free survival (EFS) and time to next treatment (TTNT) were also improved with Jaypirca, highlighting its efficacy and tolerability in difficult-to-treat cases.

Jaypirca showed superior progression-free survival and lower discontinuation rates versus standard treatments in patients with previously treated CLL or SLL.

Treatment Discontinuations Reduced With Jaypirca in CLL, SLL

The combination of Nubeqa (darolutamide) plus androgen deprivation therapy (ADT; reduces the amount of testosterone in the body) significantly improved radiographical progression-free survival (PFS; the length of time during and after treatment when a patient with cancer lives without the disease worsening) in patients with metastatic hormone-sensitive (still responds to hormone therapy) prostate cancer (mHSPC), according to results presented at the 2024 ESMO Congress.

Compared with ADT alone, the addition of the androgen receptor pathway inhibitor (ARPI; blocks activity of androgen receptor, a protein that aids cancer growth) Nubeqa reduced the risk of radiographical progression or death by 46% and demonstrated low safety risks in the phase 3 ARANOTE trial.

The ARANOTE trial demonstrated that adding Nubeqa to androgen deprivation therapy (ADT) significantly extended the time patients with metastatic hormone-sensitive prostate cancer lived without their disease worsening.

Compared to ADT alone, Nubeqa plus ADT reduced the risk of radiographic progression or death by 46%.

Nubeqa had a low risk of side effects, making it a promising treatment option for patients with prostate cancer.

The ARANOTE trial suggests that Nubeqa plus ADT could be a valuable treatment option for men with metastatic hormone-sensitive prostate cancer, especially for those who may not tolerate or benefit from traditional treatments.

The combination of Nubeqa and ADT outperformed ADT alone in terms of both efficacy and safety.

“[Nubeqa], ADT, plus docetaxel is already a standard of care for men with mHSPC and ARASENS shows that [Nubeqa] plus ADT plus docetaxel had a favorable efficacy and safety profile compared with ADT plus docetaxel in these patients,” explained Dr. Fred Saad, professor and chairman of urology and director of genitourinary oncology at the University of Montreal Hospital Center in Canada, in his presentation. “ARANOTE was designed to evaluate the role of [Nubeqa] [plus] ADT without docetaxel to hopefully provide a new treatment option for men with mHSPC.”

Despite the ARASENS trial establishing the efficacy of ARPI, ADT and chemotherapy, it was only compared with ADT plus docetaxel and Nubeqa plus ADT had not been compared with ADT alone, leading to the ARANOTE trial to determine if this combination can be a treatment option without chemotherapy.

A total of 669 patients were randomly assigned to receive Nubeqa 600 milligrams twice daily plus ADT (446 patients) or placebo plus ADT (223 patients). They must have had metastatic disease confirmed by conventional imaging or soft tissue/visceral metastases on CT or MRI assessed by central review and ECOG performance status of 0 (fully active), 1 (limited activity), or 2 (poor activity). They were stratified by presence or absence of visceral metastases (spreading of cancer to internal organs) and prior local therapy. The primary focus was radiographical PFS (rPFS) by central blinded review, with secondary focuses including overall survival (OS; time from the start of treatment when a patient with cancer is still alive), time to prostate-specific antigen (PSA; time it takes for PSA levels to rise after treatment) progression and safety.

Baseline characteristics and disease characteristics were broadly similar across the groups; Saad highlighted the approximately 30% of the population who were Asian and 10% who were Black, which enabled these groups to be studied more closely. In the Nubeqa group, 71.1% had de novo metastatic disease compared with 75.3% in the ADT alone group. Visceral disease was present in 11.9% and 12.1% of each respective group and 17.9% of each group had prior local therapy.

Primary and Secondary Efficacy End Points

At data cutoff of June 7, 2024, median follow-up was 25.3 months for the Nubeqa group and 25 months for the placebo group. The median rPFS for Nubeqa plus ADT was not reached, meaning less than half of patients did not show disease progression, compared with 25 months for placebo plus ADT. At 24 months, the rate of rPFS was 70.3% for the Nubeqa group versus 52.1% for the placebo group.

The rPFS benefit with Nubeqa was consistent across all analyzed subgroups. For patients with low disease volume, the hazard ratio (HR; a statistical measure comparing the risk of an event between two groups) was 0.3 compared with an HR of 0.6 for those with high-volume disease. Those with prior local therapy had an HR of 0.34 whereas those with no prior local therapy had an HR of 0.59.

Although OS was not mature and was not reached in both groups, the stratified HR was 0.81 favoring Nubeqa. Adding Nubeqa also showed a benefit across other secondary focuses including time to metastatic castration-resistant prostate cancer, time to PSA progression, time to initiation of subsequent systemic therapy and time to pain progression. It also led to 62.6% of patients with PSA less than 0.2 nanograms/milliliter at any time during treatment, compared with only 18.5% in the placebo group.

The median treatment duration was 24.2 months in the Nubeqa group compared with 17.3 months for the placebo group. Incidence of treatment-emergent adverse events (TEAEs; treatment induced side effects) was similar between the groups, with 91% any-grade and 30.8% grade 3 (severe) or 4 (life threatening) TEAEs with Nubeqa plus ADT and 90% any-grade and 30.3% grade 3 or 4 with ADT plus placebo. There was a rate of 4.7% grade 5 (fatal) TEAEs in the Nubeqa group versus 5.4% for the placebo group. Serious TEAEs occurred at a rate of 23.6% in the Nubeqa group versus 23.5% in the placebo group and 6.1% discontinued treatment due to TEAEs in the Nubeqa group, a lower rate than the 9% in the placebo group.

When looking at TEAEs associated with ARPIs in particular, they were similar across the groups. Fatigue, mental impairment disorder, hypertension, cardiac arrythmias, coronary artery disorders, heart failure, falls, bone fracture, vasodilation (the widening of blood vessels) and flushing, diabetes and hyperglycemia, and rash all occurred in fewer than 10% of patients in either group and exposure-adjusted incidence rate per 100 patient years was also similar in the Nubeqa and placebo groups.

“[Nubeqa] and ADT significantly improved rPFS in patients with mHSPC, showed a benefit across all secondary endpoints, [and] had a favorable safety profile, confirming previous studies using [Nubeqa],” said Saad. “We believe that Nubeqa and ADT, without the need of docetaxel, could become an additional standard of care for mHSPC.”

Adding Nubeqa to androgen deprivation therapy improved radiographic progression-free survival in patients with metastatic hormone-sensitive prostate cancer.

Nubeqa Plus ADT Outperformed ADT Alone in Treating Prostate Cancer

Patients with high-risk muscle-invasive urothelial carcinoma (MIUC) who underwent radical surgery experienced notable improvements in disease-free survival (DFS, the time a patient lives without signs of cancer) when treated with adjuvant (postsurgical) Keytruda (pembrolizumab) when compared with patients who underwent observation after a 45-month follow-up, study findings have shown.

Findings from the phase 3 AMBASSADOR trial were presented during the 2024 ESMO Annual Congress by Dr. Andrea B, Apolo, a senior investigator in the Genitourinary Malignancies Branch of the National Cancer Institute in Bethesda, Maryland.

Adjuvant Keytruda significantly extended disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) compared to observation.

The benefit of Keytruda was observed regardless of PD-L1 expression and lymph node status, suggesting its potential effectiveness for a wide range of patients.

Patients with lower tract MIUC, primarily bladder cancer, demonstrated a more significant improvement in DFS with Keytruda compared to those with upper tract disease.

While the final analysis of overall survival is pending, interim data suggest a potential benefit of Keytruda in extending the lives of patients with high-risk MIUC.

The study reported manageable toxicity associated with Keytruda, making it a promising treatment option for patients with MIUC.

Urothelial carcinoma, as defined by the National Cancer Institute, begins in the urothelial cells lining the urethra, bladder, ureters, renal pelvis and other organs, and almost all bladder cancers are urothelial carcinomas.

“In this setting, [Keytruda] doubled the median DFS at 29.6 months compared with 14.2 months in the observation arm,” Apolo said during a presentation of the data in the intention-to-treat population that was published in 

A total of 702 enrolled patients were randomly assigned to receive 200 milligrams of Keytruda every three weeks (354 patients) versus observation (348 patients) with dual primary end points of DFS and overall survival (OS, the time a patient lives regardless of disease status). Across both cohorts, the median age was 68 years, and the majority of patients were men (74.6%).

In the Keytruda arm, 57.3% of patients were PD-L1 positive compared with 57.8% of patients in the observation arm. In the Keytruda arm, the primary tumor sites were bladder (75.4%), upper tract (22.9%) and urethra (1.7%) compared with the observation arm: 75.6%, 21% and 3.4%, respectively.

When evaluating subgroups, Apolo noted that DFS in patients who were PD-L1 positive showed a benefit in terms of prognosis. “The marker was prognostic, but not predictive because both arms, PD-L1–positive and –negative, benefited from adjuvant [Keytruda],” Apolo added.

Turning to DFS for primary tumor sites in the upper and lower tract, investigators reported small numbers, “so it is hard to draw conclusions from these cohorts,” Apolo said. Exploratory DFS subgroups were also evaluated and included an evaluation of lymph node status (if the cancer has spread to the lymph nodes), upper tract neoadjuvant therapy, ECOG performance status (evaluating a patient’s ability to perform daily tasks) and histologic variants.

In all patients with N0 stage disease (cancer has not spread to the lymph nodes, with higher numbers indicating increasing spread to the lymph nodes), the hazard ratio (HR) for DFS was 0.53, meaning there was a 47% likelihood the disease would return compared with the observation group. In N1, the HR was 0.81, and for patients with N2/N3 stage disease, the HR was 0.71. “This was prognostic, but adjuvant Keytruda benefited all groups including N0 and N1, and N2 and N3,” she continued.

Evaluation of lymph node stage by lower tract versus upper tract demonstrated that “patients with disease present in the lower tract, which were predominantly bladder patients, showed benefit from adjuvant [Keytruda], regardless of N0 or N-plus status,” Apolo said. “Looking at patients with upper tract disease, we noted that the [DFS] numbers are very small and the data are inconclusive,” Apolo continued.

The investigators reported that the most common sites of metastatic disease occurrence (702 patients) were abdominal lymph nodes (40%), pelvic lymph nodes (30%), bone (22%), chest/neck lymph nodes (20%) and liver (18%). Apolo noted that these recurrence sites were “interesting and hypothesis-generating.”

In the primary analysis of the AMBASSADOR study, Keytruda showed a significant improvement in DFS versus observation after a 22-month follow-up.

DA approval of Opdivo (nivolumab) in high-risk MIUC after surgery

. At that point, 34% of patients in the observation arm and 20% of patients in the Keytruda arm had received a non-protocol checkpoint inhibitor or withdrew consent. “The interim OS had been presented, although the final analysis of OS had not been performed because only 8% of events had been reached,” Apolo said.

Apolo concluded the presentation noting that subgroup analysis showed a DFS benefit with Keytruda versus observation regardless of PD-L1 expression and lymph node status.

“Based on the doubling of the median DFS and the previously presented manageable toxicity, this trial supports adjuvant [Keytruda] as a therapeutic option in patients with high-risk MIUC,” Apolo said.

Among patients with high-risk muscle-invasive urothelial carcinoma, postsurgical Keytruda extended the time some lived without signs of cancer.

Tony Berberabe, M.P.H.

CDK4/6 Inhibitor Combos Miss Survival Goal in Metastatic Breast Cancer Subset

Treatment Discontinuations Reduced With Jaypirca in CLL, SLL

Nubeqa Plus ADT Outperformed ADT Alone in Treating Prostate Cancer

Keytruda Improves Disease-Free Survival in Some With Urothelial Carcinoma

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