The combination of nab-paclitaxel (Abraxane) and pembrolizumab (Keytruda) produced an encouraging overall response rate (ORR) with manageable safety in patients with advanced urothelial cancer who were refractory to platinum-based chemotherapy or cisplatin ineligible, according to data from the phase 2 ABLE trial (NCT03240016) presented during the 2022 Genitourinary Cancers Symposium.

At a median follow-up of 85.7 weeks (range, 26.3-194.0), nab-paclitaxel plus pembrolizumab (n = 36) elicited an unconfirmed best ORR of 55.6% (95% CI, 42%-74%) per RECIST v1.1 criteria in a total of 36 patients; this included 6 complete responses (CRs) and 14 partial responses. Moreover, 11 patients achieved stable disease, and 4 experienced disease progression. The combination was also found to result in a confirmed best ORR of 52.8%.

Anti­–PD-1/PD-L1 therapy has proven to have efficacy in patients with advanced urothelial cancer who are either refractory to platinum-based chemotherapy or ineligible to receive cisplatin. When previously examined in these populations, pembrolizumab has been found to result in a median progression-free survival (PFS) of 2 months and a median overall survival (OS) ranging from 10 to 11 months, according to data from the phase 3 KEYNOTE-361 (NCT02335424) and KEYNOTE-045 (NCT02256436) trials.

 Additionally, nab-paclitaxel has also demonstrated activity in patients with platinum-refractory advanced disease. Despite these advances, there is a need to further improve outcomes for these patients.

The single-arm, 2-stage ABLE trial enrolled patients with recurrent, unresectable locally advanced or metastatic urothelial cancer who were platinum-refractory or cisplatin-ineligible per Galsky criteria. Patients had to be at least 18 years of age, have measurable disease per RECIST v1.1 criteria, an ECOG performance status ranging from 0 to 2, and acceptable organ function. They could not have peripheral neuropathy that was higher than grade 1 in severity.

Notably, 17 patients were enrolled to participate in the first stage of the trial, and 19 additional patients were enrolled to second stage, after at least 5 responses were observed in stage 1.

Study participants were administered 200 mg of intravenous (IV) pembrolizumab on day 1, plus 125 mg/m

 of IV nab-paclitaxel on days 1 and 8 of 21-day cycles. Notably, nab-paclitaxel could be discontinued after 6 cycles per patient or investigator preference. In the second stage of the trial, the starting dose of nab-paclitaxel was dropped to 100 mg/m

 due to grade 3 or higher adverse effects (AEs), which included fatigue, peripheral neuropathy, anemia, and oral mucositis.

The primary end point of the trial was ORR by RECIST v1.1 criteria. Secondary end points included PFS, OS, CR proportion, duration of response (DOR), duration of therapy, and safety.

The median age of patients enrolled to the trial was 71.5 years (interquartile range, 65.5-77.5), and 88.9% were male. The patient population was evenly divided among those with platinum-refractory and cisplatin-ineligible disease. Of the patients who were cisplatin ineligible, 44.4% had a creatinine clearance of less than 60, 16.7% had hearing loss, 16.7% had an ECOG performance status of 2, and 22.2% had more than 1 reason for ineligibility.

The primary tumor location was the bladder in 69.4% of patients and the upper tract in 30.6% of patients. Moreover, 86.1% of patients had metastatic disease, 41.7% had visceral disease, and 52.8% underwent prior surgery. Twenty-five percent of patients had an ECOG performance status of 0, 55.6% had a status of 1, and 19.4% had a status of 2. The starting dose of nab-paclitaxel was 125 mg/m2 for 47.2% of patients, and 52.8% started that agent at 100 mg/m2. Additionally, 41.7% of patients had a Bajorin score of 0, 55.6% had a score of 1, and 2.8% had a score of 2.

Additional data showed that the combination resulted in a median PFS of 6.8 months (95% CI, 4.4–not reached [NR]), and a median OS of 18.2 months (95% CI, 10.6-NR). The median DOR with the regimen was 19.1 weeks (95% CI, 16.7- 36.3). The median duration of therapy was 16.0 weeks (range, 1-NR) for nab-paclitaxel and 21.0 weeks (range, 0-NR) for pembrolizumab.

Any grade AEs that were frequently experienced with the combination included fatigue (n = 21), anemia (n = 14), alopecia (n = 12), peripheral sensory neuropathy (n = 12), dysgeusia (n = 10), diarrhea (n = 9), pruritus (n = 8), and rash maculopapular (n = 7). The most common grade 3 to 5 toxicities were fatigue (n = 6), anemia (n = 4), peripheral sensory neuropathy (n = 3), oral mucositis (n = 3), and decreased neutrophil count (n = 2).

Notably, 7 patients discontinued treatment due to AEs. Ten patients experienced grade 3 or higher immune-mediated AEs due to pembrolizumab.

Serious toxicities experienced with the regimen included thromboembolic events (n = 3) and urinary tract infection (n = 2), as well as acute kidney injury, blurred vision, delirium, disease progression, disease progression with metastases to the brain, encephalitis, encephalopathy, fever, hiccoughs, hip fracture, hypercalcemia, pneumonia, pyelonephritis, sepsis, sinus bradycardia, and transient ischemic attack/brain ischemia (n = 1, each).

Tsung I, Green E, Palmbos P, et al. A phase 2 trial of nab-paclitaxel in combination with anti-PD1 in advanced urothelial cancer. 

 2022;40(suppl 6):502. doi:10.1200/JCO.2022.40.6_suppl.502

Arjun V Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. 

. 2017;18(11):1483-1492. doi:10.1016/S1470-2045(17)30616-2

Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. 

. 2017;376(11):1015-1026. doi:10.1056/NEJMoa1613683

Articles

Nab-paclitaxel plus pembrolizumab produced an encouraging overall response rate with manageable safety in patients with advanced urothelial cancer who were refractory to platinum-based chemotherapy or cisplatin ineligible, according to data from the phase 2 ABLE trial. 

Nab-Paclitaxel Plus Pembrolizumab Produces Promising Responses in Advanced Urothelial Cancer

Niraparib (Zejula) in combination with bevacizumab (Avastin) was efficacious following 1 line of platinum-based chemotherapy among patients with newly diagnosed advanced ovarian cancer regardless of biomarker status, according to data from an updated analysis of the phase 2 OVARIO study (NCT03326193) presented during the 2022 SGO Annual Meeting on Women’s Cancer.

Melissa Hardesty, MD, MPH, added that combination had a safety profile consistent with the known adverse effects of each treatment as monotherapy.

At the June 16, 2021, data cutoff point, patients who received the PARP inhibitor niraparib plus the vascular endothelial growth factor-A inhibitor bevacizumab (N = 105) achieved a median progression-free survival (PFS) of 19.6 months (95% CI, 16.5-25.1). The 18-month PFS rate was 62% (95% CI, 52%-71%) and the 24-month PFS rate was 53% (95% CI, 43%-63%). Median follow-up was 28.7 months (interquartile range, 23.9-32.5).

“OVARIO enrolled a high-risk population,” said Hardesty, a gynecologic oncologist with Alaska Women’s Cancer Care in Anchorage. “More than half of the patients remained progression-free at 24 months. Clinical benefit [by PFS] was observed in the overall population, and across biomarker subgroups in a continuum.”

OVARIO enrolled patients with high-grade serous or endometrioid stage IIIB to IV epithelial ovarian, fallopian tube, or peritoneal cancer. Eligible patients achieved a complete response (CR), partial response (PR), or no evidence of disease (NED) result after treatment with front-line platinum-based chemotherapy plus bevacizumab.

Patients weighing less than 77 kg and/or with a platelet count below 150,000 per µL (n = 82) received niraparib 200 mg daily plus bevacizumab 15 mg/kg once every 3 weeks. All other patients (n = 23) were treated with niraparib 300 mg daily plus bevacizumab 15 mg/kg once every 3 weeks. All patients underwent tissue testing for HRD at enrollment.

The primary end point of the trial was PFS rate at 18 months. Secondary end points included median PFS, overall survival (OS), time to first therapy, and safety. PFS rate at 6 and 12 months were exploratory end points.

The median age of patients included in the trial was 60 (range, 37-82).Most patients had and ECOG performance status of 0 (63%), stage IIIC disease at diagnosis (68%), serous histology (95%). Investigators observed HRD positivity at a rate of 47%, and 63% of patients underwent prior treatment with neoadjuvant chemotherapy or IDS debulking surgery. A majority of patients had a CR or NED to their prior surgery or chemotherapy (58%) and 42% experienced a PR.

Results showed that the median time to first subsequent treatment was 17.5 months (95% CI, 14.5-20.7). Notably, median time to second progression was not evaluable (NE; 95% CI, 32.1-NE). OS data was immature at the time of the analysis, with an event rate of 23.8%.

Investigators noted a higher median PFS patients in HRD subgroup compared with the homologous recombination proficient (HRP) and homologous recombination not determined (HRnd) subgroups, 28.3 months (n = 49; 95% CI, 19.9-NE) versus 14.2 months (n = 38; 95% CI, 8.6-16.8) and 12.1 months (n = 18; 95% CI, 8-NE), respectively. Within the HRD subgroup, patients with 

alterations (n = 29) had a median PFS of NE (95% CI, 19.3-NE), while patients with 

wild-type mutations (n = 16) had a median PFS of 28.3 months (95% CI, 12.1-NE).

No new safety signals were observed with the combination; all patients experienced a treatment-related adverse event (TRAE) of any grade. Most patients (80%) had a TRAE of at least grade 3, with 77% of these determined to be related to niraparib and 51% attributed to bevacizumab. TRAEs leading to treatment interruption, dose reduction, or treatment discontinuation were reported in 88%, 74%, and 40% of patients, respectively.

The most common TRAEs of any grade included thrombocytopenia (70%), fatigue (57%), anemia, and nausea (both 52%). Commonly occurring TRAEs grade 3 or higher included thrombocytopenia (39%), anemia (34%), and hypertension (27%), among others.

Investigators also noted that treatment with niraparib plus bevacizumab resulted in no clinically meaningful impact on patient quality of life; the baseline score was 25.7 (standard deviation [SD], 3.79) with a mean change from baseline of -0.7 (SD, 0.35).

“There was no impact on quality of life as assessed by change in FOSI [Functional Assessment of Cancer Therapy-Ovarian Symptom Index] score,” Hardesty concluded.

Hardesty M, Krivak T, Wright GS, et al. OVARIO, a phase 2 study of niraparib + bevacizumab in advanced ovarian cancer following front-line platinum-based chemotherapy with bevacizumab: updated analysis. Presented at: SGO Annual Meeting on Women’s Cancer; March 18 -21, 2022; Phoenix, AZ. Abstract 40.

Niraparib in combination with bevacizumab was efficacious following 1 line of platinum-based chemotherapy among patients with newly diagnosed advanced ovarian cancer, regardless of biomarker status.

Niraparib Plus Bevacizumab Shows Promise in High-Risk Ovarian Cancer Population

The oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859) did not improve progression-free survival (PFS) per independent central review vs physician’s choice of endocrine treatment in patients with locally advanced or metastatic, estrogen receptor (ER)–positive, HER2-negative breast cancer who progressed on or following hormonal therapies, missing the primary end point of the phase 2 AMEERA-3 trial (NCT04059484).

Notably, the toxicity profile of the agent proved to be consistent with what has been observed in prior studies, with no new safety signals reported.

“This phase 2 trial evaluated amcenestrant as a monotherapy in a patient population with advanced disease where limited treatment options remain,” John Reed, MD, PhD, head of research and development at Sanofi, stated in a press release. “While we are disappointed with the AMEERA-3 results, we continue to investigative amcenestrant in patients with earlier stages of breast cancer with different tumor profiles and where different standard-of-care treatments are used.”

The international, prospective, open-label, randomized trial was launched to evaluate the safety and efficacy of the SERD in patients with ER-positive, HER2-negative metastatic or locally advanced breast cancer that was progressing on 6 or more months of continuous endocrine therapy.

 Patients had to be at least 18 years of age and could not have received more than 1 prior chemotherapeutic or targeted regimen for advanced or metastatic disease. Notably, previous treatment with CDK inhibitors was permitted.

If patients had an ECOG performance status of 2 or higher, a life expectancy of less than 3 months, had concomitant illness and factors potentially impacting the absorption of amcenestrant, they were excluded.

The target enrollment for the trial was 282 patients. Participants were randomized 1:1 to receive either the SERD orally at a once-daily dose of 400 mg or physician’s choice of endocrine therapy, which could have included single-agent treatment with fulvestrant (Faslodex), tamoxifen, or an aromatase inhibitor (AI). Treatment was administered in 28-day cycles until intolerable toxicity, disease progression, death, or patient request.

Patients were stratified based on the presence of visceral metastases, whether they previously received CDK4/6 inhibitors, and their ECOG performance status.

The primary end point of the trial was PFS per RECIST v1.1 criteria, and key secondary end points included overall survival, response rate, duration of response, clinical benefit rate, pharmacokinetics, quality of life, and safety.

Sanofi, the drug developer, shared plans to continue to evaluate data from AMEERA-3 and publish the full results in the future.

Previously, amcenestrant was evaluated both as a single agent and in combination with targeted therapies in patients with ER-positive, HER2-negative metastatic breast cancer, as part of the phase 1/2 AMEERA-1 trial (NCT03284957).

 The trial enrolled postmenopausal patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer with measurable disease and who received at least 6 months of previous endocrine therapy in the advanced setting or who had resistance to adjuvant endocrine therapy.

Patients could not receive more than 1 prior line of chemotherapy for advanced disease, nor could they have received more than 2 prior lines of endocrine therapy for advanced disease in part D. Patients also could not have received more than 1 prior CDK4/6 inhibitor for advanced disease in part C. Those in part D were not allowed to receive any CDK4/6 inhibitors, PI3K inhibitors, or AKT inhibitors. Patients needed to have an ECOG performance status that was less than 2.

At the 2021 ASCO Annual Meeting data from parts C and D of the trial were reported. In part C, the dose-escalation cohort was comprised of 15 patients who received amcenestrant at a once-daily dose of 200 mg (n = 9) or 400 mg (n = 6) in 28-day cycles. In part D, the dose-expansion cohort was comprised of 30 patients who received the agent at the recommended phase 2 dose (RP2D) established in part C, but in combination with a standard dose of palbociclib (Ibrance), which was 125 mg for 21 days on, and 7 days off.

Among the 39 patients who comprised parts C and D, the median age was 59 years (range, 33-86), 74.4% had an ECOG performance status of 0, 84.6% had secondary resistance to endocrine therapy, and 59.0% received immediate prior therapy for advanced disease.

Moreover, 41.0% did not receive any prior lines of therapy in advanced settings, although 38.5% received 1 prior line. Moreover, 43.6% and 41.0% of patients, respectively, received 0 or 1 prior lines of endocrine therapy in advanced settings. Regarding prior treatment received in advanced settings, 23.1% previously received chemotherapy, 59.0% received endocrine therapy, and 15.4% received targeted therapy.

Data showed that in response-evaluable patients who received amcenestrant at the RP2D and who did not previously receive CDK4/6 inhibitors or mTOR inhibitors, the objective response rate was 34.3% (95% CI, 21.1%-49.6%), which included a partial response rate of 34.3%. Moreover, 62.9% of patients achieved stable disease and 2.9% experienced disease progression. The clinical benefit rate in these patients was 74.3% (95% CI, 59.4%-85.9%).

Regarding safety, no dose-limiting toxicities were reported, and no dose reductions of the SERD were required. However, 25.6% of patients required at least 1 dose reduction of palbociclib to 100 mg, and 4 of these patients needed a subsequent reduction to 75 mg.

A total of 3 patients discontinued treatment because of toxicity, 2 of which were determined to be associated with study treatment. Amcenestrant and palbociclib treatment-related adverse effects were experienced by 71.8% and 89.7% of patients, respectively; these effects were grade 3 or higher in 15.4% and 46.2% of patients, respectively. One patient had a grade 3 serious toxicity of deep vein thrombosis that was found to be related to the SERD.

Amcenestrant is currently under evaluation in the phase 3 AMEERA-5 trial (NCT04478266), which was designed to determine whether the addition of amcenestrant to palbociclib would improve PFS vs letrozole plus palbociclib in patients with ER-positive, HER2-negative advanced breast cancer who have not previously received systemic therapy for advanced disease.

Additionally, the phase 3 AMEERA-6 trial (NCT05128773), is evaluating the safety and efficacy of amcenestrant vs tamoxifen in patients with hormone receptor–positive early breast cancer who discontinued an adjuvant AI because of treatment-related toxicity.

Sanofi provides update on phase 2 study evaluating amcenestrant in ER+/HER2- advanced or metastatic breast cancer. News release. Sanofi; March 14, 2022. Accessed March 14, 2022. 

Phase 2 study of amcenestrant (SAR439859) versus physician’s choice of locally advanced or metastatic ER-positive breast cancer (AMEERA-3). ClinicalTrials.gov. Updated March 7, 2022. Accessed March 14, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04059484

Tolaney S, Cicin I, Betancourt R, et al. AMEERA-3, a phase 2 trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (her2-), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies. 

. 2021;81(suppl 4):OT-09-09. doi:10.1158/1538-7445.SABCS20-OT-09-09

Chandarlapaty S, Linden HM, Neven P, et al. AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with palbociclib (palbo) in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). 

. 2021;39(suppl 15):1058. doi:10.1200/JCO.2021.39.15_suppl.1058

Amcenestrant did not improve progression-free survival per independent central review vs physician’s choice of endocrine treatment in select patients with locally advanced or metastatic, estrogen receptor–positive, HER2-negative breast cancer, missing the primary end point of the phase 2 AMEERA-3 trial.

Pipeline Report: March 2022

Articles

Nab-Paclitaxel Plus Pembrolizumab Produces Promising Responses in Advanced Urothelial Cancer

Niraparib Plus Bevacizumab Shows Promise in High-Risk Ovarian Cancer Population