Merck is pleased to announce that KEYTRUDA, in combination with platinum and fluorouracil (FU), has been approved by the FDA for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).
KEYTRUDA has also been approved by the FDA as a single agent for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.
| • | PD-L1 diagnostic testing is required prior to initiating monotherapy with KEYTRUDA in patients with metastatic or with unresectable, recurrent HNSCC. |
Prior Indication:
KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.
This prior indication has not changed.
FDA=Food and Drug Administration; PD-L1=programmed death ligand 1.
| Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg | ||
| • | Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information below. | |
KEYNOTE-048
First-line treatment of metastatic or unresectable, recurrent HNSCC
The efficacy of KEYTRUDA was investigated in KEYNOTE-048 (NCT02358031), a randomized, multicenter, open-label, active-controlled trial conducted in 882 patients with metastatic HNSCC who had not previously received systemic therapy for metastatic disease or with recurrent disease who were considered incurable by local therapies. Patients with active autoimmune disease that required systemic therapy within two years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by tumor PD-L1 expression (tumor proportion score [TPS] ≥50% or <50%) according to the PD-L1 immunohistochemistry (IHC) 22C3 pharmDx kit, human papillomavirus (HPV) status according to p16 IHC (positive or negative), and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. 1). Patients were randomized 1:1:1 to one of the following treatment arms:
| • | KEYTRUDA 200 mg intravenously every 3 weeks |
| • | KEYTRUDA 200 mg intravenously every 3 weeks, carboplatin area under the curve (AUC) 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) |
| • | Cetuximab 400 mg/m2 intravenously as the initial dose then 250 mg/m2 intravenously once weekly, carboplatin AUC 5 mg/mL/min intravenously every 3 weeks or cisplatin 100 mg/m2 intravenously every 3 weeks, and FU 1000 mg/m2/day as a continuous intravenous infusion over 96 hours every 3 weeks (maximum of 6 cycles of platinum and FU) |
Treatment with KEYTRUDA continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at Week 9 and then every 6 weeks for the first year, followed by every 9 weeks through 24 months. A retrospective re-classification of patients’ tumor PD-L1 status according to CPS using the PD-L1 IHC 22C3 pharmDx kit was conducted using the tumor specimens used for randomization.
The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by BICR according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) sequentially tested in the subgroup of patients with CPS ≥20, the subgroup of patients with CPS ≥1, and the overall population.
The study population characteristics were: median age of 61 years (range: 20 to 94), 36% age 65 or older; 83% male; 73% White, 20% Asian and 2.4% Black; 61% ECOG PS of 1; and 79% were former/current smokers. Twenty-two percent of patients’ tumors were HPV-positive, 23% had PD-L1 TPS ≥50%, and 95% had Stage IV disease (Stage IVA 19%, Stage IVB 6%, and Stage IVC 70%). Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1 and 43% had CPS ≥20.
The trial demonstrated a statistically significant improvement in OS for patients randomized to KEYTRUDA in combination with chemotherapy compared to those randomized to cetuximab in combination with chemotherapy at a pre-specified interim analysis in the overall population. The trial also demonstrated a statistically significant improvement in OS for the subgroup of patients with PD-L1 CPS ≥1 randomized to KEYTRUDA as a single agent compared to those randomized to cetuximab in combination with chemotherapy. At the time of the interim analysis, there was no significant difference in OS between the KEYTRUDA single agent arm and the control arm for the overall population. The table below summarizes efficacy results for KEYTRUDA in combination with chemotherapy.
Efficacy Results for KEYTRUDA plus Platinum/Fluorouracil in KEYNOTE-048
| Endpoint | KEYTRUDA
200 mg every 3 weeks Platinum n=281 |
Cetuximab
Platinum FU n=278 |
| OS | ||
| Number (%) of patients with event | 197 (70%) | 223 (80%) |
| Median in months (95% CI) | 13.0 (10.9, 14.7) | 10.7 (9.3, 11.7) |
| Hazard ratio* (95% CI) | 0.77 (0.63, 0.93) | |
| p-Value† | 0.0067 | |
| PFS | ||
| Number of patients with event (%) | 244 (87%) | 253 (91%) |
| Median in months (95% CI) | 4.9 (4.7, 6.0) | 5.1 (4.9, 6.0) |
| Hazard ratio* (95% CI) | 0.92 (0.77, 1.10) | |
| p-Value† | 0.3394 | |
| Objective Response Rate | ||
| ORR‡ (95% CI) | 36% (30.0, 41.5) | 36% (30.7, 42.3) |
| Complete response rate | 6% | 3% |
| Partial response rate | 30% | 33% |
| Duration of Response | ||
| Median in months (range) | 6.7 (1.6+, 30.4+) | 4.3 (1.2+, 27.9+) |
| *Based on the stratified Cox proportional hazard model |
| †Based on stratified log-rank test |
| ‡Response: Best objective response as confirmed complete response or partial response |
CI=confidence interval; ORR=objective response rate.
In KEYNOTE-048, OS hazard ratios (HRs) for patients randomized to KEYTRUDA in combination with chemotherapy, compared with cetuximab in combination with chemotherapy, were similar for all populations regardless of PD-L1 expression in a pre-specified interim analysis: intent-to-treat (ITT) (HR 0.77, 95% CI: 0.63, 0.93), CPS ≥1 (HR 0.71, 95% CI: 0.57, 0.88), CPS ≥20 (HR 0.69, 95% CI: 0.51, 0.94).
The table below summarizes efficacy results for KEYTRUDA as a single agent in the subgroup of patients with CPS ≥1 HNSCC and CPS ≥20 HNSCC.
Efficacy Results for KEYTRUDA as a Single Agent in KEYNOTE-048 (CPS ≥1 and CPS ≥20)
| Endpoint | CPS ≥1 | CPS ≥20 | ||
| KEYTRUDA
200 mg every n=257 |
Cetuximab
Platinum FU n=255 |
KEYTRUDA
200 mg every n=133 |
Cetuximab
Platinum FU n=122 |
|
| OS | ||||
| Number of events (%) | 177 (69%) | 206 (81%) | 82 (62%) | 95 (78%) |
| Median in months (95% CI) | 12.3 (10.8, 14.9) | 10.3 (9.0, 11.5) | 14.9 (11.6, 21.5) | 10.7 (8.8, 12.8) |
| Hazard ratio* (95% CI) | 0.78 (0.64, 0.96) | 0.61 (0.45, 0.83) | ||
| p-Value† | 0.0171 | 0.0015 | ||
| PFS | ||||
| Number of events (%) | 225 (88%) | 231 (91%) | 113 (85%) | 111 (91%) |
| Median in months (95% CI) | 3.2 (2.2, 3.4) | 5.0 (4.8, 5.8) | 3.4 (3.2, 3.8) | 5.0 (4.8, 6.2) |
| Hazard ratio‡(95% CI) | 1.15 (0.95, 1.38) | 0.99 (0.75, 1.29) | ||
| Objective Response Rate | ||||
| ORR‡ (95% CI) | 19% (14.5, 24.4) | 35% (29.1, 41.1) | 23% (16.4, 31.4) | 36% (27.6, 45.3) |
| Complete response rate | 5% | 3% | 8% | 3% |
| Partial response rate | 14% | 32% | 16% | 33% |
| Duration of Response | ||||
| Median in months (range) | 20.9 (1.5+, 34.8+) | 4.5 (1.2+, 28.6+) | 20.9 (2.7, 34.8+) | 4.2 (1.2+, 22.3+) |
| *Based on the stratified Cox proportional hazard model |
| †Based on stratified log-rank test |
| ‡Response: Best objective response as confirmed complete response or partial response |
In an exploratory subgroup analysis for patients with CPS 1-19 HNSCC, the median OS was 10.8 months (95% CI: 9.0, 12.6) for KEYTRUDA as a single agent and 10.1 months (95% CI: 8.7, 12.1) for cetuximab in combination with chemotherapy, with an HR of 0.90 (95% CI: 0.68, 1.18).
Recommended Dosage for HNSCC
The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
When administering KEYTRUDA in combination with chemotherapy, administer KEYTRUDA prior to chemotherapy when given on the same day. Refer to the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA for recommended dosing information, as appropriate.
Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg (continued)
| Immune-Mediated Pneumonitis | |||
| • | KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of HNSCC patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grades 3-5 in 1.5% of patients. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis. | ||
| Immune-Mediated Colitis | |||
| • | KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis. | ||
| Immune-Mediated Hepatitis | |||
| • | KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA. | ||
| Immune-Mediated Endocrinopathies | |||
| • | KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients. | ||
| • | Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia. | ||
| Immune-Mediated Nephritis and Renal Dysfunction | |||
| • | KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis. | ||
| Immune-Mediated Skin Reactions | |||
| • | Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA. | ||
| Other Immune-Mediated Adverse Reactions | |||
| • | Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. | ||
| • | The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use. | ||
| • | Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients. | ||
| Infusion-Related Reactions | |||
| • | KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. | ||
| Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) | |||
| • | Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions. | ||
| • | In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients. | ||
| Increased Mortality in Patients With Multiple Myeloma | |||
| • | In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a programmed death receptor-1 (PD-1) or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials. | ||
| Embryofetal Toxicity | |||
| • | Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose. | ||
| Adverse Reactions | |||
| • | In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%). | ||
| • | In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%). | ||
| • | In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. | ||
| Lactation | |||
| • | Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose. | ||
Before prescribing KEYTRUDA® (pembrolizumab), please read the Prescribing Information.
The Medication Guide also is available.
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The new policy is aimed at increasing transparency and vehemently opposed by industry. The new policy will apply to drugs or biologics with list prices greater than $35 for a month’s supply or the normal course of therapy, which HHS Secretary Alex Azar said is what consumers would be accustomed to pay because it’s close to an insurance plan’s average copayment for these drugs. First proposed in October, the rule will be going into effect in July.
FDA=Food and Drug Administration; PD-L1=programmed death ligand 1.
Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg
First-line Treatment of Advanced RCC in Combination With Axitinib
The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”).
Patients were randomized (1:1) to one of the following treatment arms:
Treatment with KEYTRUDA and axitinib continued until Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter.
The study population characteristics were: median age of 62 years (range: 26 to 90); 38% age 65 or older; 73% male; 79% White and 16% Asian; 19% and 80% of patients had a baseline Karnofsky Performance Scale (KPS) of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate and 13% poor.
The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review (BICR) according to modified RECIST v1.1. Additional efficacy outcome measures included overall response rate (ORR), as assessed by BICR. A statistically significant improvement in OS was demonstrated at the pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvement in PFS and ORR. The table below summarizes the efficacy results for KEYNOTE-426. The median follow-up time was 12.8 months (range 0.1 to 22.0 months). Consistent results were observed across pre-specified subgroups, IMDC risk categories and PD-L1 tumor expression status.
| Endpoint | KEYTRUDA with axitinib n=432 |
Sunitinib n=429 |
| OS | ||
| Number of patients with event (%) | 59 (14%) | 97 (23%) |
| Median in months (95% CI) | NR (NR, NR) | NR (NR, NR) |
| Hazard ratio* (95% CI) | 0.53 (0.38, 0.74) | |
| p-Value† | <0.0001‡ | |
| 12-month OS rate | 90% (86, 92) | 78% (74, 82) |
| PFS | ||
| Number of patients with event (%) | 183 (42%) | 212 (49%) |
| Median in months (95% CI) | 15.1 (12.6, 17.7) | 11.1 (8.7, 12.5) |
| Hazard ratio* (95% CI) | 0.69 (0.57, 0.84) | |
| p-Value† | 0.0001§ | |
| ORR | ||
| Overall confirmed response rate (95% CI) |
59% (54, 64) | 36% (31, 40) |
| Complete response | 6% | 2% |
| Partial response | 53% | 34% |
| p-Value¶ | <0.0001 | |
| *Based on the stratified Cox proportional hazard model
†Based on stratified log-rank test ‡p-Value (one-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for final analysis). §p-Value (one-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for final analysis). ¶Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region NR=not reached CI=confidence interval. |
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The recommended dose of KEYTRUDA is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks in combination with 5 mg axitinib orally twice daily until disease progression, unacceptable toxicity, or for KEYTRUDA, up to 24 months in patients without disease progression. When axitinib is used in combination with KEYTRUDA, dose escalation of axitinib above the initial 5 mg dose may be considered at intervals of six weeks or longer. See also the Prescribing Information for recommended axitinib dosing information.
Immune-Mediated Pneumonitis
Immune-Mediated Colitis
Immune-Mediated Hepatitis, or Hepatotoxicity (in Combination With Axitinib)
Immune-Mediated Hepatitis
Hepatotoxicity (in Combination With Axitinib)
Immune-Mediated Endocrinopathies
Immune-Mediated Nephritis and Renal Dysfunction
Immune-Mediated Skin Reactions
Other Immune-Mediated Adverse Reactions
Infusion-Related Reactions
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Increased Mortality in Patients With Multiple Myeloma
Embryofetal Toxicity
Adverse Reactions
Lactation
Before prescribing KEYTRUDA® (pembrolizumab), please read the Prescribing Information.
The Medication Guide also is available.
AstraZeneca is pleased to announce that IMFINZI® (durvalumab) injection has been assigned a unique HCPCS code by the Centers for Medicare & Medicaid Services (CMS).
Effective for dates of services on or after January 1, 2019, J-Code J9173 can be used to identify IMFINZI® (durvalumab) when billing across settings of care as noted in the Medicare Program.
For updated information, please check:
Merck is pleased to announce that KEYTRUDA has been approved by the FDA for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic MCC. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
· PD-L1 diagnostic testing is not required prior to initiating treatment with KEYTRUDA in these patients.
FDA=Food and Drug Administration; PD-L1=programmed death ligand 1.
Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg
· Immune-mediated adverse reactions, which may be severe or fatal, can occur with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered if appropriate. For more information regarding immune-mediated adverse reactions, please read the additional Selected Safety Information below.
KEYNOTE-017
The efficacy of KEYTRUDA was investigated in Study KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were objective response rate (ORR) and duration of response as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Among the 50 patients, the median age was 71 years (range: 46 to 91 years), with 80% age 65 or older; 68% male; 90% White; and Eastern Cooperative Oncology Group (ECOG) performance score (PS) was 0 (48%) and 1 (52%). Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.
Efficacy results are summarized below.
Efficacy Results in KEYNOTE-017
| Endpoint |
KEYTRUDA 2 mg/kg every 3 weeks n=50 |
| Objective Response Rate | |
| ORR (95% CI) | 56% (41, 70) |
| Complete response (CR) rate (95% CI) | 24% (13, 38) |
| Partial response (PR) rate (95% CI) | 32% (20, 47) |
| Duration of Response | |
| Range in months* | 5.9-34.5+ |
| Patients with duration ≥6 months, n (%) | 27 (96%) |
| Patients with duration ≥12 months, n (%) | 15 (54%) |
| * | The median duration of response was not reached. CI=confidence interval. |
Recommended Dosage for MCC
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.
Selected Safety Information for KEYTRUDA® (pembrolizumab) injection 100 mg(continued)
Immune-Mediated Pneumonitis
· KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%), and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.
Immune-Mediated Colitis
· KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.
Immune-Mediated Hepatitis
· KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.
Immune-Mediated Endocrinopathies
· KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.
· Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.
Immune-Mediated Nephritis and Renal Dysfunction
· KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.
Immune-Mediated Skin Reactions
· Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.
Other Immune-Mediated Adverse Reactions
· Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.
· The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials and postmarketing use.
· Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.
Infusion-Related Reactions
· KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.
Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
· Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.
· In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.
Increased Mortality in Patients With Multiple Myeloma
· In clinical trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a programmed death receptor-1 (PD-1) or PD-L1 blocking antibody in this combination is not recommended outside of controlled clinical trials.
Embryofetal Toxicity
· Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.
Adverse Reactions
· The most common adverse reactions for KEYTRUDA (reported in ≥20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
Lactation
· It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.
Pediatric Use
· There is limited experience in pediatric patients. In a study in 40 pediatric patients with advanced melanoma, lymphoma, or PD-L1–positive advanced, relapsed, or refractory solid tumors, the safety profile was similar to that seen in adults treated with KEYTRUDA. Toxicities that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%), and hyponatremia (18%).
AstraZeneca is pleased to announce that IMFINZI® (durvalumab) injection has been assigned a unique HCPCS code by the Centers for Medicare & Medicaid Services (CMS).
Effective for dates of services on or after January 1, 2019, the following code can be used to identify IMFINZI® (durvalumab) when billing across settings of care as noted in the Medicare Program: Changes to Hospital Outpatient Prospective Payment and Ambulatory Surgical Center Payment Systems and Quality Reporting Programs available at:
https://s3.amazonaws.com/public-inspection.federalregister.gov/2018-24243.pdf
U.S. Food and Drug Administration today granted accelerated approval to Calquence (acalabrutinib) for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
U.S. Food and Drug Administration today approved Yescarta (axicabtagene ciloleucel), a cell-based gene therapy, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Yescarta, a chimeric antigen receptor (CAR) T cell therapy, is the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).
On September 22, 2017, the Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Co.) for the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib.
