Nichole Tucker

The FDA has accepted a supplemental Biologics License Application (sBLA) submitted for neoadjuvant pembrolizumab (Keytruda) combined with chemotherapy and adjuvant pembrolizumab monotherapy for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC).

The sBLA was accepted for a standard review and was given a Prescription Drug Fee User target action date of March 29, 2021.

“There is a real need to advance new treatment options for triple-negative breast cancer, an aggressive form of the disease. The FDA’s acceptance of these KEYTRUDA applications for review is an important step toward helping patients with both early-stage and metastatic disease,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, in a statement. “These acceptances mark the first United States applications for KEYTRUDA in breast cancer, and we look forward to working closely with the FDA to bring these new options to patients as quickly as possible.”

The application was submitted based on results from 2 clinical trials, the phase 3 KEYNOTE-355 trial, and the phase 3 KEYNOTE-522 trial. KEYNOTE-355 was conducted in 847 patients with previously untreated locally recurrent inoperable or metastatic TNBC and KEYNOTE-522 was conducted in 784 patients with early TNBC. Both studies were randomized and double-blind. KEYNOTE-355 was also placebo-controlled and assessing the co-primary end points, progression-free survival (PFS), and overall survival (OS). The secondary end points of the study include objective response rate, duration of response, disease control rate, and safety.

The coprimary end points of KEYNOTE-522 was partial complete response (PCR) rate and event-free survival (EFS). The study also explored PCR at time of definitive surgery, OS, and EFS.

Efficacy of Pembrolizumab Plus Chemotherapy

Results from KEYNOTE-355 were presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. As previously reported by 

, KEYNOTE-355 showed a trend toward progression-free survival benefit with the combination of pembrolizumab plus nab-paclitaxel chemotherapy compared to chemotherapy alone. The trend was consistent in the cohorts of patients with PD-L1 CPS ≥ 10, PD-L1 CPS ≥ 1, and in the intent-to-treat (ITT) population.

Two-hundred fifteen PFS events were observed in the PD-L1 CPS ≥ 10 cohort. The median PFS was 9.7 months in the pembrolizumab/chemotherapy arm compared with 5.6 months in the single-agent arm (HR, 0.65; 95% CI, 0.49-0.86; one-sided 

The PD-L1 CPS ≥ 1 cohort had 450 PFS events. Median PFS was 7.6 months for the pembrolizumab/chemotherapy arm versus 5.6 months for the chemotherapy arm (HR, 0.74; 95% CI, 0.61-0.90; one-sided 

 =.0014). The PFS results were not statistically significant, according to the prespecified criteria.

Patients in the ITT cohort showed 602 PFS events with a median PFS of 7.5 months in the pembrolizumab arm versus 5.6 months with chemotherapy alone (HR, 0.82; 95% CI, 0.69-0.97).

In KEYNOTE-522, an efficacy benefit was also observed with pembrolizumab in terms of PCRs in the pembrolizumab plus chemotherapy arm versus the single-agent arm. Specifically, complete responses were observed in 64.8% of patients in the combination arm versus 51.2% in the chemotherapy arm. The result met the prespecified criteria for statistical significance in favor of pembrolizumab plus chemotherapy.

The positive result observed in the general population of patients in KEYNOTE-522 was also seen across the subgroup populations enrolled in the study. In detail, pembrolizumab plus chemotherapy benefitted patients regardless of nodal status, tumor size, PD-L1 status, age, and ECOG performance score.

Safety of Pembrolizumab Plus Chemotherapy

Patients treated with the pembrolizumab combination and chemotherapy in KEYNOTE-355 experienced a similar number of treatment-related adverse events (AEs; 96.3% vs. 95%, respectively). About 68% of patients treated with pembrolizumab plus chemotherapy had grade 3-5 treatment-related AEs were seen in versus 66.9% of those who received chemotherapy alone. Not many treatment-related AEs led to death in the pembrolizumab arm, and there were none in the single-agent chemotherapy arm. For any study drug, 18.1% of treatment-related AEs led to discontinuation in the pembrolizumab arm, as did 11.0% in the chemotherapy arm.

The most common AEs in the pembrolizumab and control arms included anemia (48.9% vs. 45.9%), neutropenia (41.1% vs. 38.1%), nausea 39.3% vs. 40.9%, alopecia (33.1% vs. 33.5%), fatigue (28.5% vs. 29.5%), neutrophil count decrease (22.2% vs. 26.3%), and alanine transferase increase (20.5% vs. 16.4%).

In KEYNOTE-522, 99.0% of the combination arm and 99.7% of the monotherapy arm experienced any-grade AEs. Treatment-related AEs were mostly observed during the neoadjuvant phase, compared with the adjuvant phase. The most common treatment-related AEs in the combination arm versus the chemotherapy arm were nausea (62.7 v vs. 63.2%), alopecia (60.3% vs. 56.6%), and anemia (55.1% vs. 55.3%).

In addition to accepting the sBLA for pembrolizumab combined with chemotherapy and adjuvant pembrolizumab monotherapy for the treatment of patients with high-risk early-stage TNBC, the FDA also granted Priority Review to a 

sBLA for the combination of pembrolizumab and chemotherapy, as patients with metastatic TNB

1. Merck Announces Two US Regulatory Milestones for KEYTRUDA® (pembrolizumab) in Triple-Negative Breast Cancer (TNBC). News release. Merck. July 30, 2020. Accessed July 30, 2020. 

2. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol 2020: 38 (suppl; abstr 1000). doi: 10.1200/JCO.2020.38.15_suppl.1000

3. Schmid P, Cortes J, Pusztai H, et al. Pembrolizumab for early triple-negative breast cancer. 

. 2020. 382(19):810-21. DOI: 10.1056/NEJMoa1910549

Articles

The FDA has accepted a supplemental Biologics License Application submitted for neoadjuvant pembrolizumab combined with chemotherapy and adjuvant pembrolizumab monotherapy for the treatment of patients with high-risk early-stage triple-negative breast cancer.

FDA Approval Being Considered for Neoadjuvant/Adjuvant Pembrolizumab +/- Chemo in Early TNBC 

The FDA accepted a supplemental Biologics License Application (sBLA) for and granted Priority Review to pembrolizumab (Keytruda) in combination with chemotherapy, which is intended for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (combined positive score [CPS] ≥10), Merck announced in a press release.

“There is a real need to advance new treatment options for triple-negative breast cancer, an aggressive form of the disease. The FDA’s acceptance of these Keytruda applications for review is an important step toward helping patients with both early-stage and metastatic disease,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, in a statement about two applications for FDA approval. “These acceptances mark the first US applications for Keytruda in breast cancer, and we look forward to working closely with the FDA to bring these new options to patients as quickly as possible.”

The FDA has set a target action date of November 28, 2020 under the Prescription Drug User Fee Act for a final decision on the application.

Data from the phase 3 KEYNOTE-355 trial support the sBLA. The results, which were presented by Javier Cortes, MD, PhD, during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, showed that pembrolizumab in combination with different chemotherapy partners led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) when compared with chemotherapy alone.

In the study, 847 patients were randomized 2:1 to receive either intravenous (IV) pembrolizumab administered at 200 mg every 3 weeks plus chemotherapy (n = 556) or chemotherapy alone (n = 281). Chemotherapy regimens consisted of IV nab-paclitaxel (Abraxane) at 100 mg/m2 on days 1, 8, and 15 every 4 weeks; IV paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 4 weeks; or gemcitabine 1000 mg/m2 and carboplatin AUC 2 on days 1 and 8 every 3 weeks. Patients in each arm were divided into cohorts comprised of individuals with PD-L1 expression of CPS ≥10, CPS ≥1, and the intention-to-treat (ITT) population.

The CPS ≥10 cohort had 215 PFS events across both study arms. The median PFS was 9.7 months in the pembrolizumab/chemotherapy arm compared with 5.6 months in the chemotherapy-alone arm (HR, 0.65; 95% CI, 0.49-0.86; one-sided 

The cohort with CPS ≥1 had 450 PFS events with a median PFS of 7.6 months in the pembrolizumab-plus-chemotherapy arm versus 5.6 months in the chemotherapy arm (HR, 0.74; 95% CI, 0.61-0.90; one-sided 

 = .0014). The PFS results did not meet the prespecified criteria for statistical significance.

Finally, in the ITT cohort, 602 PFS events occurred. The median PFS observed with the pembrolizumab combination was 7.5 months versus 5.6 months with chemotherapy alone (HR, 0.82; 95% CI, 0.69-0.97).

Overall, the pembrolizumab arm was favored in terms of PFS. This was observed across the subgroup population, with some variances in the CPS <1 group and the CPS <10 groups.

In terms of safety, treatment-related adverse events (AEs) occurred in 96.3% of patients in the combination arm versus 95% in the chemotherapy-alone arm. Grade 3-5 treatment-related AEs were seen in 68.1% of patients treated with pembrolizumab plus chemotherapy versus 66.9% of those who received chemotherapy alone. Few treatment-related AEs led to death in the pembrolizumab arm and there were none in the chemotherapy arm. For any study drug, 18.1% of treatment-related AEs led to discontinuation in the pembrolizumab arm, as did 11.0% in the chemotherapy arm.

The most common any-grade AEs in the combination and chemotherapy arms included anemia (48.9% vs 45.9%), neutropenia (41.1% vs 38.1%), nausea (39.3% vs 40.9%), alopecia (33.1% vs 33.5%), fatigue (28.5% vs 29.5%), neutrophil count decrease (22.2% vs 26.3%), and alanine aminotransferase increase (20.5% vs 16.4%).

Immune-mediated AEs occurred in 25.6% of patients in the pembrolizumab group compared with 6.0% in the chemotherapy group. Grade 3 to 5 immune-mediated AEs were seen in 5.2% of patients in the combination arm but in no percentage of the chemotherapy arm. There were no deaths caused by immune-mediated AEs, but 3.9% of the patients in the pembrolizumab arm and 1.1% in the chemotherapy arm did discontinue treatment of any drug due to these AEs.

Based on these findings, Cortes et al noted that there may be a role for the combination of pembrolizumab and chemotherapy as frontline treatment of patients with metastatic TNBC.

KEYNOTE-355 is an ongoing, randomized, double-blind, placebo-controlled study assessing the coprimary end points of PFS and overall survival in patients with metastatic TNBC. The secondary end points of the study include objective response rate, duration of response, disease control rate, and safety.

Prior to the submission and acceptance of the sBLA for this agent as treatment of metastatic TNBC, the FDA granted a Breakthrough Therapy designation to pembrolizumab plus chemotherapy as neoadjuvant treatment of patients with high-risk, early-stage TNBC based on data from KEYNOTE-522 (NCT03036488), the first randomized trial of an anti–PD-L1 agent in the neoadjuvant and adjuvant setting of TNBC.

1. Merck announces two us regulatory milestones for keytruda® (pembrolizumab) in triple-negative breast cancer (tnbc). News release. Merck. July 30, 2020. Accessed July 30, 2020.

https://www.businesswire.com/news/home/20200730005275/en

The FDA accepted a supplemental Biologics License Application for and granted Priority Review to pembrolizumab in combination with chemotherapy, which is intended for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1.

Pembrolizumab Plus Chemotherapy on the Road to FDA Approval for mTNBC, Granted Priority Review

The FDA has granted a Breakthrough Therapy designation to osimertinib (Tagrisso) as adjuvant treatment of patients with stage IB-IIIA 

-mutated non–small cell lung cancer (NSCLC) following complete tumor resection with curative intent, AstraZeneca announced in a press release.

The Breakthrough Therapy designation for osimertinib was granted on the basis of positive results from the phase 3 ADAURA clinical trial (NCT02511106), which were presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. The trial showed a statistically significant and clinically meaningful improvement in disease-free survival (DFS) for this patient population.

“The historic magnitude of the DFS benefit seen in ADAURA speaks to the impact osimertinib has on the lives of patients with 

-mutated NSCLC after receiving surgery and appropriate adjuvant chemotherapy,” the study’ lead investigator, Roy Herbst, MD, PhD, Ensign Professor of Medicine, professor of Pharmacology, chief of Medical Oncology, and associate Director for Translational Research at Yale Comprehensive Cancer Center, told 

In the study, osimertinib was administered to 339 patients at a dose level of 80 mg, once daily and compared with placebo. A total of 343 patients were treated in the placebo arm. Both study arms continued treatment until disease recurrence, completion, or due to other discontinuation criteria being met. Follow-up was conducted on weeks 12 and 24, followed by every 24 weeks to 5 years and yearly, until disease recurrence. After recurrence, follow-up was every 24 weeks for 5 years, then yearly.

The study population was stratified by stage of disease, type of 

), and race (Asian vs. non-Asian). According to the American Joint Committee on Cancer staging, 31 patients in the osimertinib arm were diagnosed as stage IB at baseline, while 35 were stage II, and 34 were stage IIIA. In the placebo group, 31 patients were stage IB, 34 were stage II, and 35 were stage IIIA. Most patients in the study had 

 mutations, including 55 patients in the osimertinib arm and 56 in the placebo arm. This left 45 patients in the osimertinib arm with 

 mutations and 44 in the placebo arm. The majority of the patient population was Asian versus non-Asian, including 64 in each arm, while 36 in each arm were non-Asian.

The median DFS in patients with stage II/IIIA disease, the study’s primary end point, was not reached in the osimertinib arm (95% CI, 38.8-not calculated) compared with 20.4 months (95% CI, 16.0-24.5) in the placebo arms (HR, 0.17; 95% CI, 0.12-0.23; 

 <.0001). The data had reached 33% maturity at the time they were presented during ASCO. In the overall study population, the median DFS was also not reached in the osimertinib arm compared with 28.1 months (95% CI, 22.1-35.8) in the placebo arm (HR, 0.21; 95% CI, 0.16-0.28; 

 <.0001). The data were 29% mature at the time they were reported.

The subgroup analysis showed good DFS hazard ratios, which were consistent with the primary analysis. The hazard ratios ranged from 0.21 to 0.50. The clinical benefit favoring osimertinib was observed across the subgroup populations.

The 2-year DFS rate was also calculated by stage, showing a rate of 87% 95% CI, 77%-93%) in patients with stage IB disease who received osimertinib compared to 73% (95% CI, 62%-81%) in the placebo arm HR, 0.50; 95% CI, 0.25-0.96). For stage II patients, the DFS rate was 91% (95% CI, 82%-95%) in the osimertinib arm versus 56% (95%. CI, 45%-65%) in the placebo arm (HR, 0.17; 95% CI, 0.08-0.31). Finally, among patients with stage IIIA disease, the DFS rate was 88% (95% CI, 79%-94%) in the osimertinib arm versus 32% (95% CI, 23%-42%) in the placebo arm (HR, 0.12; 95% CI, 0.07-0.20).

Most patients in the study experienced an adverse event (AE), regardless of study treatment. Any-grade AEs specifically occurred in 97% of patients who received osimertinib compared with 89% who received placebo. Grade 3 or higher AEs were observed in 20% of the osimertinib group compared with 145 of the placebo group. Serious AEs were also seen in the study in 16% of the osimertinib-treated patients and 13% of those who received placebo.

AEs of any grade led to discontinuation of treatment in 11% of patients in the osimertinib arm versus 4% in the placebo arm. Dose reductions caused by any-grade AEs occurred in 7% of the osimertinib arm and 1% of the placebo arm.

The most common AEs observed in osimertinib group versus the placebo group were diarrhea (46% vs. 19%), paronychia (25% vs. 1%), dry skin (23% vs. 6%), and pruritis (19% vs. 9%), respectively. Overall osimertinib demonstrated a tolerable safety profile.

The Breakthrough Therapy Designation is another step towards osimertinib receiving FDA approval for this indication. Due to the high recurrence rate among these patient, the drug has the potential to fill a treatment gap in the landscape.

“The ADAURA trial has shown osimertinib to be a new practice changing therapy for patients with 

-positive stage I-III NSCLC- preventing recurrent in both local and metastatic sites.”

1. Tagrisso granted Breakthrough Therapy Designation in the US for the adjuvant treatment of patients with Stage IB-IIIA EGFR-mutated lung cancer. News release. AstraZeneca. July 30, 2020. Accessed July 30, 2020. 

2. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. 

 2020: 38 (suppl; abstr LBA5). doi: 10.1200/JCO.2020.38.18_suppl.LBA5

The FDA granted Breakthrough Therapy designation to osimertinib as adjuvant treatment of patients with stage IB-IIIA EGFR-mutated non–small cell lung cancer following complete tumor resection with curative intent.

FDA Grants Breakthrough Therapy Designation to Osimertinib in EGFR+ Lung Cancer

The combination of pembrolizumab (Keytruda) plus nab-paclitaxel demonstrated clinically meaningful and sustainable responses, along with prolonged progression-free survival (PFS) when administered as salvage therapy to patients with metastatic urothelial carcinoma (mUC), according to results from the phase 2 PEANUT study.

Preliminary research showed an objective response rate (ORR) of 27.7% with nab-paclitaxel given as monotherapy in the second-line setting to patients with mUC. Since pembrolizumab has become the standard of care for patients with mUC after prior chemotherapy failure, there was rationale to combine the agents as treatment of this patient population.

PFS per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) was the primary end point of the study. The secondary end points explored were safety/tolerability, duration of response (DOR), and overall survival (OS). The study was 90% powered to detect a minimum 3.0-month improvement in PFS up to a 5.0-month improvement.

The median PFS was 5.9 months (95% CI, 3.1-11.5), meeting the primary end point of the study. Pembrolizumab plus nab-paclitaxel also led to an ORR of 38.6% (95% CI, 27.2%-51.0%). Complete responses were observed in 10 patients (14.3%; 95% CI, 7.1%-24.7%), partial responses (PRs) were observed in 17 patients (24.3%), and unconfirmed PRs were noted in 8 patients (11.4%). Eighteen patients (25.7%) in the study had stable disease from the combination treatment, and progressive disease was seen in 17 patients (24.3%).

The median DOR was not reached (NR) in the study (95% CI, 11.5-NR). According to PET/CT scans, responses included the absence of residual pathologic of FDG-uptake in 17.1% of patients, a decrease in FDG-uptake in 25.7%, and no response or increase in FDG-uptake in 50% of patients.

The median OS was also NR in the study (95% CI, 9.5-NR).

Patients in the study were followed for a median of 9.8 months. The median time to response was 1.4 months. Notably, responses were maintained in 24 patients who received the combination regimen, and of those patients, ongoing responses lasting more than 12 months were observed in 5 patients.

In the first 12 patients in the study, no serious adverse events (AEs) or grade 3/4 AEs were observed. In the overall study population, AEs of any grade occurred in 87.1%, treatment-related AEs occurred in 84.3%, and of that, 81.4% were related to treatment with nab-paclitaxel and 35.7% were related to pembrolizumab. Serious AEs of any grade occurred in 15.7% of the overall population.

Overall, 11 patients discontinued treatment, 2.9% due to both therapies, 24.3% to nab-paclitaxel, and 1.4% due to pembrolizumab.

The study findings led to a question during the 35th Annual European Association of Urology Congress of whether the combination of pembrolizumab and nab-paclitaxel could be switch maintenance after frontline chemotherapy in this patient population. Andrew Neechi, MD, the presenter of the PEANUT data, noted that it is a possibility.

The PEANUT study was an open-label, single-arm clinical trial (NCT03464734). Intravenous (IV) pembrolizumab 200 mg was administered to patients on day 1 of treatment and IV nab-paclitaxel 125 mg/m2 was administered on days 1 and 8, every 3 weeks. Treatment in the study was continued until loss of benefit, unacceptable toxicity, or investigator decision or withdrawal by the patient.

Eligible patients were those with histologically confirmed UC of the bladder or the urothelium, measurable disease per RECIST v1.1, and an ECOG performance status of 0 or 1. Patients must have failed 1 or 2 cisplatin-based conventional chemotherapy regimens for metastatic disease. Prior chemotherapy could include neoadjuvant or adjuvant regimens if the patient relapsed within 6 months of the last cycle of chemotherapy.

According to baseline screening, the median age of patients in the study was 67 years (range, 60-73). Female patients made up 26% of the population. The ECOG performance status was calculated as 0 in 69% of patients and 1 in 31% of patients. In terms of histology at baseline, 81% of patients had pure UC, 11% had UC and squamous cell carcinoma, 4% were diagnosed with UC and glandular component, and 3% had other variants of the disease. Most of the study participants were former smokers (59%), but 27% never smoked while 14 were current smokers. The site of the primary tumor in the study was most commonly the bladder (84.3%), followed by the urinary tract (14.3%) and the urethra (1.4%).

Baseline disease characteristics showed visceral disease in 58.6% of patients, along with lung metastases in 22.9%, liver metastases in 28.6%, and bone metastases in 28.6%. In addition, 32.9% of patients had lymph node-only disease. Hemoglobin level of <10 gr/dL was observed in 13% of patients. The Bellmunt prognostic risk factors score varied in patients, but most patients (50%) had a score of 0, followed by 1 in 29% of the population, 2 in 20% of patients, and 3 in 1%.

The number of prior therapies was 1 for 76% of patients and 2 for the remaining 24%. Prior treatment included neoadjuvant or adjuvant chemotherapy in 39% of patients and radical removal of the primary tumor in 69%.

Twenty-nine percent of patients had a history of previous non-muscle-invasive UC, and 19% had previous Bacillus Calmette-Guerin instillations.

Neechi A, Raggi D, Bandini M, et al. Interim results of PEANUT: An open-label, single-arm, phase 2 study evaluating pembrolizumab plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC). Presented at: 35th Annual European Association of Urology Congress; July 20-26, 2020; Virtual. Poster 1056.

The combination of pembrolizumab plus nab-paclitaxel demonstrated clinically meaningful and sustainable responses, along with prolonged progression-free survival when administered as salvage therapy to patients with metastatic urothelial carcinoma.

Author | Nichole Tucker

Articles

FDA Approval Being Considered for Neoadjuvant/Adjuvant Pembrolizumab +/- Chemo in Early TNBC

Pembrolizumab Plus Chemotherapy on the Road to FDA Approval for mTNBC, Granted Priority Review

FDA Grants Breakthrough Therapy Designation to Osimertinib in EGFR+ Lung Cancer

Pembrolizumab Plus Nab-Paclitaxel May Be an Option for Switch Maintenance Following Chemo in mUC