Health Canada has granted conditional approval for KEYTRUDA® (pembrolizumab), Merck's anti-PD-1 therapy, in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) in adults whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) and who have not received prior chemotherapy for metastatic disease. This conditional approval is based on the results of the pivotal Phase 3 KEYNOTE-355 trial which demonstrated KEYTRUDA®'s ability to improve progression-free survival (PFS) in combination with chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin), as compared to chemotherapy alone.

KEYTRUDA Is Now Approved in Combination With Chemotherapy as First-Line Treatment for Patients With Locally Recurrent Unresectable or Metastatic TNBC Whose Tumors Express PD-L1 (CPS ≥10) and Who Have Not Received Prior Chemotherapy for Metastatic Disease

Merck...today announced that KEYTRUDA, Merck’s anti-PD-1 therapy, has received two new approvals from the Japan Pharmaceuticals and Medical Devices Agency (PMDA). KEYTRUDA is approved for the treatment of patients with PD-L1-positive, hormone receptor-negative and human epidermal growth factor receptor 2 (HER2)-negative, inoperable or recurrent breast cancer, based on the results of the Phase 3 KEYNOTE-355 trial.

KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated...Triple-Negative Breast Cancer (TNBC)...in combination with chemotherapy, for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA approved test.

First Line...PD-L1 CPS ≥10g regardless of germline BRCA mutation...Pembrolizumab + chemotherapy (albumin bound paclitaxel, paclitaxel, or gemcitabine and carboplatin)...

Pembrolizumab is used with chemotherapy in adults with triple negative breast cancer whose tumours express PD-L1 with a combined positive score (CPS - the number of PD-L1 positive cells in relation to tumour cells) greater than or equal to 10...

Recommendations...Patients with metastatic triple-negative breast cancer with expression of programmed cell death ligand-1 (PD-L1–positive) and no existing contraindications may be offered the addition of immune checkpoint inhibitor to chemotherapy (atezolizumab plus nab-paclitaxel or pembrolizumab plus chemotherapy) as first-line therapy...

Among patients with PD-L1 CPS ≥10 tumors, the ORR per RECIST version 1.1 by blinded independent central review was 42% (95% CI, 20–67) in the pembrolizumab plus chemotherapy group and 33% (95% CI, 7–70) in the placebo plus chemotherapy group….In Japanese patients enrolled in KEYNOTE-355, pembrolizumab plus chemotherapy tended to show improvements in OS and PFS with manageable toxicity versus placebo plus chemotherapy, consistent with the global population.

In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab-chemotherapy group...Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone.

For adjuvant therapies, the ORR (OR=1.26, P=0.04) of atezolizumab/pembrolizumab plus chemotherapy was higher in the intention to treat (ITT) arms than the placebo groups in TNBC….We collate evidence of atezolizumab/pembrolizumab as viable therapeutics among patients with TNBC with PD-L1 subgroups deriving higher benefits.

For OS, results in the CPS 1-9 subgroup showed comparable efficacy for pembro + chemo and placebo + chemo...For OS, results in the CPS 1-9 subgroup showed comparable efficacy for pembro + chemo and placebo + chemo; however, results in the CPS 10-19 and CPS ≥20 subgroups showed a similar treatment benefit with the addition of pembro...

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) in adults whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10) and who have not received prior chemotherapy for metastatic disease.

Pembro + chemo significantly improved OS vs chemo alone in pts with CPS ≥10 tumors...Pembro + chemo improved ORR in pts with CPS ≥10 tumors….Pembro + chemo showed a statistically significant and clinically meaningful improvement in OS vs chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 (CPS ≥10).

Pembro + chemo improved ORR in pts with CPS ≥10 tumors. For all endpoints, the pembro treatment effect increased with PD-L1 enrichment....Pembro + chemo showed a statistically significant and clinically meaningful improvement in OS vs chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 (CPS ≥10).

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced positive overall survival (OS) results from the pivotal Phase 3 KEYNOTE-355 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with chemotherapy for the treatment of patients with metastatic triple-negative breast cancer (mTNBC).

...phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy....Pembrolizumab–chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo–chemotherapy among patients with metastatic triple-negative breast cancer...

Pts with de novo or locally recurrent inoperable/metastatic TNBC with disease-free interval ≥6 mo were randomized 2:1 to pembro vs pbo (up to 35 administrations) + chemo (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) until completion or progression/toxicity.... Median follow-up was 25.7 mo. Pembro + chemo improved PFS vs chemo in the ITT pop...pembro + chemo showed clinically meaningful improvement in PFS vs chemo in the ITT pop and in PD-L1–positive pts enrolled in Asia...

...median follow-up was 25.9 mo for pembro + chemo (n=566) and 26.3 mo for pbo + chemo (n=281). The HR for PFS favored pembro regardless of choice of chemo or CPS population (Table). Results for the key secondary endpoints of ORR, DCR, and DOR favored pembro + chemo, with the treatment effect increasing as CPS increased (Table)...

...PD-L1 as a predictive biomarker of pembrolizumab efficacy in metastatic TNBC...ORR was 9.7% (30/309) with pembrolizumab and 11.3% (33/292) with chemotherapy when PD-L1 expression status was not considered...In the pembrolizumab arm, the area under the ROC curve (AUROC; 95% CI) was 0.69 (0.58-0.80) for tumor samples scored for CPS, 0.66 (0.55-0.77) for QID, and 0.55 (0.46-0.64) for TPS...

Pts were ≥18 y with stage IV/M1 TNBC that progressed on or after 1-2 prior treatments...Pts were randomly assigned 1:1 to pembro...Approximately half of pts had PD-L1+ tumors (CPS ≥1, n=103 [57%]; CPS ≥10, n=46 [25%]; CPS ≥20, n=24 [13%]). Median OS with pembro vs chemo was 15.6 vs 17.8 mo in pts with CPS ≥10, 12.2 vs 15.1 mo in pts with CPS ≥1, 11.6 mo vs 13.8 mo in all pts, and 23.5 vs 19.1 mo in pts with CPS ≥20.

...Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has accepted two new supplemental Biologics License Applications (sBLAs) for KEYTRUDA, Merck’s anti-PD-1 therapy. The FDA has accepted and granted priority review for a new sBLA seeking accelerated approval for KEYTRUDA in combination with chemotherapy 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), based on the Phase 3 KEYNOTE-355 trial.

The HRQoL population included all-comers (P, n = 306; CT, n = 288), subjects with PD-L1 positive CPS≥1 tumors (P, n = 188; CT, n = 183), and subjects with PD-L1 positive CPS≥10 tumors (P, n = 86; CT, n = 91)...Importantly, TTD in the GHS/QoL scale was longer for P compared to CT (4.3 months vs 1.7 months; HR 0.70; 95%CI; 0.46, 1.05) in the CPS-enriched population....In this CPS-enriched population of patients with mTNBC receiving second and third-line treatments, HRQoL was better for patients receiving P than those receiving CT.

Pembro + chemo significantly improved PFS vs chemo alone in pts with CPS ≥10 tumors (Table), meeting one of the protocol-defined primary objectives....Pembro combined with several chemo partners showed a statistically significant and clinically meaningful improvement in PFS vs chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 (CPS ≥10).

KEYTRUDA plus chemotherapy significantly improved PFS versus chemotherapy alone in patients whose tumors expressed PD-L1 with CPS ≥10 (HR = 0.65 [95% CI, 0.49-0.86], p=0.0012). In patients whose tumors expressed PD-L1 with CPS ≥1, statistical significance for KEYTRUDA plus chemotherapy was not met, but KEYTRUDA plus chemotherapy improved PFS in this patient population versus chemotherapy alone (median PFS = 7.6 months versus 5.6 months; HR = 0.74 [95% CI, 0.61-0.90], p=0.0014).

...Overall Survival (OS) in subjects with PD-L1 positive tumors 2. ...

...pCR rate using an alternative definition, ypT0 ypN0 (i.e., no invasive or noninvasive residual in breast or nodes) at the time of definitive surgery`pCR rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery`EFS in participants with tumors expressing PD-L1`pCR rate using an alternative definition, ypT0/Tis (i.e., absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement) at the time of definitive surgery`Overall survival (OS)`Percentage of participants who experience an adverse event (AE)`Percentage of participants who discontinue study treatment due to an AE`European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) score`EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) score...

...Overall Survival (OS)`Overall Response Rate (ORR)`Clinical Benefit Rate (CBR)`Immune-related response`Immune-related clinical benefit rate`Time to New Metastases (TTNM)`ORR in relation to PDL-1 expression`CBR in relation to PDL-1 expression...

...- Patients must have a minimum of five, available unstained formalin-fixed paraffin-embedded (FFPE) slides (4-5 micron thickness) from the residual (post-neoadjuvant) invasive tumor in primary site or lymph node; (these will be submitted to a central laboratory to determine PD-L1 expression); the tumor tissue must be adequate for PD-L1 testing, which typically requires a minimum of 100 cancer cells per slide; local PD-L1 results, even if available, will...

...- Has provided recently or newly obtained core or excisional biopsy from a locally recurrent inoperable or metastatic tumor lesion for central determination of TNBC status and PD-L1 expression, unless contraindicated due to site inaccessibility and/or participant safety concerns....

...The Number of Patients With Clinical Complete Response (cCR)`Enumeration of T Cells and Immune Cell Subsets`Evaluation of Expression of Protein Programmed Death-Ligand 1 (PD-L1) Within Tumor, Stroma, and Infiltrating Immune Cells Combined, at Baseline and Following Immunotherapy.`...

...- Has PD-L1-positive mTNBC....

In metastatic triple-negative breast cancer (TNBC), the efficacy of immune checkpoint inhibitors (ICIs)...We analyzed six overall survival (OS) curves from three RCTs. In patients with ≥1% positivity, atezolizumab was found to determine a significantly better OS than pembrolizumab. As regards pembrolizumab, adopting a threshold of PD-L1 positivity ≥10% (as opposed to ≥1%) improved median survival to a remarkable extent (23.0 vs 15.5 months).

This phase 1b/2 study examined eribulin plus pembrolizumab as a potential mTNBC... Patients with PD-L1+ tumors (combined positive score {greater than or equal to}1) had numerically higher ORR than those with PD-L1− tumors, particularly in stratum 1 (stratum 1: 34.5% [95% CI: 17.9-54.3] vs 16.1% [95% CI: 5.5-33.7]...The study-drug combination showed promising antitumor activity in the 1–3L setting.

ERI + PEMBRO has activity in pts with mTNBC. There was a trend toward more robust activity for the combination among patients with PD-L1+ tumors compared to PD-L1- tumors in the first-line setting (Stratum 1); whereas, in the later-line setting (Stratum 2) similar survival outcomes were observed among the PD-L1+ and PD-L1- pts.

In this small population, using a prototype assay scoring PD-L1 expression as the percentage of inflammatory and tumor cells staining for PD-L1, there was evidence of an increasing probability of response (one-sided P = .028 for ORR) and a reduction in the hazard (one-sided P = .012 for PFS) with increasing expression of PD-L1....Using a prototype assay, there was a trend toward clinical benefit with pembrolizumab and increasing PD-L1 expression.