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Pembrolizumab

Pembrolizumab approved as a treatment for patients with advanced or unresectable melanoma following progression on prior therapies.

Approved as first line agent in melanoma

Trade name Keytruda.

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The first PD-1 inhibitor to gain approval in the United States.

Approved as first line therapy in combination with carboplatin and pemetrexed in nonsquamous metastatic NCCLC, regardless of PD-L1 expression.

Approved in the second line setting for tumors that express 1% of PD-L1, which represents approximately 75% of patients with lung cancer.

Approved as the first line setting for patients with NSCLC who have more than 50% PT-L1 expression, making up approximally 30% of cases.

Approved for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives.

Approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Anti-PD-1 therapy for the treatment of patients with recurrent or metastatic cervical cancer on or after chemotherapy whose tumors express PD-L1.

Pembrolizumab is now the first anti-PD-1 therapy approved for the treatment of advanced cervical cancer, providing an important new second-line option.

KEYNOTE-826 randomized clinical trial found that affine pembrolizumab to chemotherapy with or without Bevacizumab improved overall survival across sub groups of patients  with persistent, recurrent, or metastatic cervical cancer.

The FDA has approved the use of pembrolizumab plus chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer who have PD-L1 expression identified via an FDA-approved test.

This approval is based on the KEYNOTE-158 trial.

In the phase 3 randomized, double-blind, placebo-controlled KEYNOTE-826 trial investigators assessed the use of pembrolizumab, paclitaxel and cisplatin or carboplatin, with or without bevacizumab in patients with first-line metastatic persistent recurrent cervical cancer who had not received treatment with chemotherapy. 

The overall response rates for the pembrolizumab and placebo regimens were 68% and 50% in both arms, respectively, with a median duration of response of 18.0 months and 10.4 months in each respective group.

For the patients whose tumors expressed PD-L1, the objective response rate was 14.3 percent with a complete response rate of 2.6 percent and partial response rate of 11.7 percent.

A highly selective humanized monoclonal IgG4 antibody directed against the PD-1 receptor on the cell surface.

The drug blocks the PD-1 receptor, preventing binding and activation of PD-L1 and PD-L2.

Causes the activation of T-cell mediated immune responses against tumor cells.

FDA approval was based on response rates demonstrated in clinical trial data from 173 patients with melanoma in the KEYNOTE-001 study.

At the recommended dose for pembrolizumab of 2 mg/kg, the overall response rate (ORR) was 24%, with a response duration lasting from 1.4 to 8.5 months.

2 mg/kg given once every 3 weeks.

Phase Ib KEYNOTE-001 study examined pembrolizumab in 276 patients with ipilimumab-naive (n = 102) and refractory (n = 173) melanoma.

In the above study, patients received treatment with pembrolizumab at 2 mg/kg or 10 mg/kg every 3 weeks.

KEYNOTE-001 study for patients treated with the 2 mg/kg dose, the ORR was 26% , with a disease control rate of 51%.

The estimated progression-free survival rate at 24 weeks was 44% with the 2 mg/kg dose and 37% with 10 mg/kg pembrolizumab.

The median overall survival (OS) for patients treated with the 2 mg/kg dose had not yet been reached at the data cuttoff. However, in the 10 mg/kg arm, the median OS was 18 months.

The 12-month OS rate was 58% with 2-mg/kg pembrolizumab and 63% with the 10-mg/kg dose.

Pembrolizumab treatment among patients with advanced melanoma is associated with an overall objective response of 33%, twelve-month progression free survival of 35%, the median overall survival of 23 months, and grade 3 or 4 treatment related adverse events occurred in 14% (Ribas A).

Adjuvant therapy for high-risk stage III melanoma, 200 mg of pembrolizumab administered every 3 weeks for up to 1 year resulted in significantly longer recurrence-free survival than placebo, with no new toxic effects identified.

The most common side effects were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.

Pembrolizumab was discontinued as a result of adverse reactions in 9% of patients.

At the 2-mg/kg dose, the discontinuation rate was 6%.

Immune-mediated adverse reactions included pneumonitis (2.9%), colitis (1%), hepatitis (0.5%), hypophysitis (0.5%), nephritis (0.7%), hyperthyroidism (1.2%), and hypothyroidism (8.3%).

Pembrolizumab, a humanized PD-1 antibody binds with high affinity to its PD-1 receptor and has significant activity in PDL-1-positive triple negative breast cancer.

In patients with early triple negative breast cancer, neoadjuvant Pembrolizumab plus chemotherapy, followed by adjuvant Pembrolizumab after surgery, resulted in significantly longer event free survival than neoadjuvant chemo therapy alone.

Among patients with TNBC, the percentage of patients with pathological complete response is significantly higher among patients who receive  pembrolizumab plus neoadjuvant chemo therapy than among those who receive placebo plus neoadjuvant chemo therapy ( Schmidt P).

The addition of pembrolizumab to polychemotherapy improves outcomes in patients with high risk early stage triple negative breast cancer: this regimen is highly efficacious with higher complete pathological response rates, and clinically meaningful improvements in event free survival.

The combination of Pembrolizumab and chemotherapy is associated with significant high-grade treatment related toxicity.

The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1).

HER2-positive breast cancers have been observed to contain high levels of T-cell infiltration.

Tumor-infiltrating lymphocytes (TILs) are associated with improved prognosis and higher response rates to trastuzumab and chemotherapy, suggesting that modulating anti-tumor immunity could further improve survival outcomes.

With a median follow-up of 13.6 months, the cohort of patients having tumors positive for PD-L1 achieved an overall response rate of 15.2% and a disease control rate of 24%.

The response rate was almost eight times higher in patients who had at least 5% of the stromal area densely infiltrated with TILs.

Among patients with HER2-negative breast cancer, PD-L1 is not as a strong predictive biomarker.

Patients with high TILs or immune infiltration usually have high levels of PD-L1 expression on their TILs.

Patients having 5% or more TILs were dramatically more likely to have a response.

TIL levels vary, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.

May be efficacious in HER2 positive breast cancer patients with PD-L1 positive tumors and resistant to trastuzumab.

Pembrolizumab is approved for patients with mismatch repair deficient or microsatellite instability high breast cancers accounting for only 2% of breast cancers.

Pembrolizumab had a 86% response rate in patients with Hodgkin’s disease that failed brentuximab.

In classic Hodgkin’s disease treatment among relapsed and refractory patients associated with an overall response rate of 69% and a complete remission rate of 22.4% (Chen R).

Pembrolizumab yielded significantly better outcomes compared with ipilimumab (Yervoy) in a randomized phase III trial of patients with advanced melanoma.

The anti-PD-1 antibody pembrolizumab produced broad and durable responses in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).

Overall response rate (ORR) of 25%, and it proved active in both HPV-positive and HPV-negative patients.with head and neck cancer.

Pembrolizumab seems to be roughly twice as effective, when measured by response as cetuximab in head and neck cancer.

KEYNOTE-102 study pembrolizumab administered at 10 mg/kg every 2 weeks, had a 20% response rate in patients with advanced HNSCC whose tumors were PD-L1 positive.

In the above study, 117 patients with head and neck cancer receiving 200 mg of pembrolizumab IV every 3 weeks 56% of patients showed some decrease in tumor size and 24.8% demonstrated objective response 24.8% demonstrated stable disease with a median time to response of 9 weeks.

First-line therapy options for head and neck cancer should now include immunotherapy with pembrolizumab given alone or in combination with chemotherapy (CT), as indicated by the results of the KEYNOTE-48 trial.

The data support pembrolizumab plus platinum-based CT and pembrolizumab monotherapy as new first-line standard-of-care therapies for relapsed/metastatic head and neck squamous cell carcinoma.

KEYNOTE-48 was a randomized, open-label study that enrolled 882 patients with recurrent/metastatic HNSCC, which was incurable with local therapies.

In treatment of non-small cell lung cancer the objective response rate was 19.4% the median duration of response of 12.5 months (baron EB et al).

In the above study patients with a score of 50% of tumor cells with PD-L1 expression the response rate was 45.2%, medium progression free survival was 6.3% months and the median overall survival was not reached.

In the KEYNOTE-010 randomized controlled trial in non–small cell lung cancer it was found to prolong overall survival and has a favorable benefit to risk profile and patients previously treated, PD-L1 positive advanced disease.

Patients with PD-L1 positive NSCLC demonstrated a 45.5% objective response rate to pembrolizumab compared to 29.8% with chemotherapy in the phase III KEYNOTE-24 trial.

Pembrolizumab in NSCLC with >50% PD-1 expression associated with progression free survival of 10.3 months compared with chemotherapy of 6 months in treatment naive advanced metaststic patients.

In the phase three KEYNOTE-407 study on squamous NSCLC, chemotherapy with pembrolizumab had a significantly longer overall survival and progression severe free survival than with chemo therapy alone.

In the KEYNOTE-010 trial, 35% of patients with relapsed nonsmall cell lung cancer (NSCLC) treated with pembrolizumab were still alive at 3 years, according to long-term results from a pivotal clinical trial.

KEYNOTE-671 trial: patients with stage II, IIIA, IIIB received four cycles of neoadjuvant, pembrolizumab or placebo in addition to chemotherapy, followed by surgical resection: event, free survival, and possible overall survival benefit are emerging, increased pathological complete response, and major pathological response as well.

Among the 10% of patients who completed all 35 cycles of pembrolizumab, the 3-year overall survival was approximately 99%, with progression-free survival (PFS) at around 70%.

 

KEYNOTE-010 trial, conducted in more than 1000 patients with NSCLC who had progressed on chemotherapy, randomized to receive immunotherapy with pembrolizumab or chemotherapy with docetaxel.

 

Overall survival at 3 years was 35% in patients with PD-L1 expression ? 50% in the tumor, and 23% in those with PD-L1 ? 1%.

This compares with 3-year overall survival of 11-13% with docetaxel.

Pembrolizumab approved for classic HD with relapsed disease-overall response rate of 69%.

In myeloma when added to dexamethasone in combination with lenalidomide or pomalidomide associated with an increased relative risk of death.

Considered therapy for microsatellite instability-high metastatic colorectal cancer.

Evidence of efficaciousness in gastric and gastro esophageal junction cancers, with objective response rate of 11.6%.

Approved for patients with recurrent locally advanced or metastatic gastric or gastrointestinal junction adenocarcinoma or squamous cell cancers whose tumors express programmed cell death ligand PD-L!.

Has antitumor activity for osteosarcoma.

Active in Richter’s tranformation but not in CLL.

Approved for the treatment of patients with hepatocellular carcinoma who have previously received sorafenib.

In the Keynote-045 study Pembrolizumab was compared to chemotherapy in patients with metastatic urothelial cancer after platinum based chemotherapy progression: Pembrolizumab median overall survival was 10.3 months versus chemotherapy 7.4 months. The overall response rate was 21% with Pembrolizumab versus 11% for cytotoxic therapy.

The combination of pembrolizumab and eribulen in the ENHANCE/Keynote-150 study demonstrated a 26.45 response rate in metastatic TNBC.

In combination with axitinib in advanced renal cell carcinoma in treatment naive patients the response rate was 73% and median progression free survival exceeded 20 months.

Axitinib with Pembrolizumab in advanced renal carcinoma resulted in significantly longer overall survival and progression free survival and a high response rate in treatment with sunitinib (Rini B).

In the Keynote 564 study Pembrolizumab treatment led to a significant improvement in disease free survival as compared with placebo after surgery among patients with kidney cancer who were high risk for recurrence (77.3 vs 68.1% at 24 months.

In the above stay the estimated percentage of patients who remained alive a 24 months was 96.6% in the Pembrolizumab Group and 93.5% in the placebo group.

Adjuvant pembrolizumab is associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo,  among participants with clear cell renal cell carcinoma at increased risk for recurrence after surgery.

KEYNOTE 189 phase III trial, the combination of Pembrolizumab with standard chemotherapy in the front line setting reduced the risk of death by more than 50% of patients with non-squamous NSCLC without EGFR or ALK mutations.

In the above trial demonstrated a significant benefit in overall survival for chemotherapy plus Pembrolizumab with an estimated 12 month overall survival rate of 69.2% versus 49.4% for chemotherapy alone.

In KEYNOTE 189 trial PD-1 overall survival was improved irrespective PD-L1 status.

KEYNOTE-180 Study demonstrated Pembrolizumab has modest activity in patients heavily pre-treated metastatic esophageal cancer.

 

The phase 3 KEYNOTE-590 trial, pembrolizumab was approved for use in patients with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma, 

when used in combination with platinum and fluoropyrimidine-based chemotherapy.

The FDA has granted an accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma.

FDA granted accelerated approval to pembrolizumab for the treatment of patients who have metastatic small cell lung cancer (SCLC) that progresses on or after platinum-based chemotherapy and at least one other line of therapy.

The FDA approved pembrolizumab for the treatment of patients with bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for, or have elected not to undergo, cystectomy.

In the KEYNOTE – 361 study a randomized trial of Pembrolizumab alone or combined with Chemotherapy versus Chemotherapy as first line therapy for advance urothelial carcinoma did not significantly improve efficacy and should not be adopted for treatment of advanced urothelial carcinoma.

KEYNOTE-057 trial which enrolled 148 patients with high-risk NMIBC, 96 of whom had BCG-unresponsive CIS with or without papillary tumors.

Patients received 200 mg of pembrolizumab every three weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease for up to 24 months.

The complete response rate in the 96 patients with high-risk BCG-unresponsive NMIBC with CIS was 41%, and median response duration was 16.2 months.

Nearly half of responding patients (46%) experienced a complete response lasting at least 12 months.

The most common adverse reactions (incidence ?10%) in patients who received pembrolizumab in KEYNOTE-057 were fatigue, diarrhea, rash, pruritus, musculoskeletal pain, hematuria, cough, arthralgia, nausea, constipation, urinary tract infection, peripheral edema, hypothyroidism and nasopharyngitis.

The FDA approved pembrolizumab for the treatment of patients with bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for, or have elected not to undergo, cystectomy.

KEYNOTE-057 trial which enrolled 148 patients with high-risk NMIBC, 96 of whom had BCG-unresponsive CIS with or without papillary tumors.

Patients received 200 mg of pembrolizumab every three weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease for up to 24 months.

The complete response rate in the 96 patients with high-risk BCG-unresponsive NMIBC with CIS was 41%, and median response duration was 16.2 months.

Nearly half of responding patients (46%) experienced a complete response lasting at least 12 months.

Pembrolizumab (Keytruda) approved for patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation.

 

Pembrolizumab monotherapy demonstrated robust, durable antitumor activity in patients with locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma (CSCC), according to a second phase 2 KEYNOTE-629 trial.

 

KEYNOTE-629 trial, patients who were administered intravenous pembrolizumab at 200 mg every 3 weeks until progressive disease.

 

Results showed an ORR of 34% with pembrolizumab. 

 

The median response duration had not yet been reached.

 

The pivotal phase 3 KEYNOTE-775/Study 309 trial evaluating the use of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) met its dual primary end points of overall and progression-free survival in patients with advanced endometrial cancer.

 

Patients had advanced endometrial cancer following at least 1 prior platinum-based regimen.

 

Positive results were reported in the mismatch repair proficient (pMMR) subgroup and patients whose disease is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

 

Pembrolizumab plus lenvatinib demonstrated a statistically significant and clinically meaningful improvement in OS, PFS, and response rate versus chemotherapy treatment of physician’s choice of doxorubicin or paclitaxel.

 

Approved as first line therapy on the basis of data from the KEYNOTE-158 trial in patients with a tumor mutational burden of 10 or more, regardless of tumor type.

 

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