U.S. Food and Drug Administration approved pembrolizumab (KEYTRUDA, Merck & Co., Inc.) for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.
This is the first FDA approval of a checkpoint inhibitor for first-line treatment of lung cancer. This approval also expands the indication in second-line treatment of lung cancer to include all patients with PD-L1-expressing NSCLC.
The FDA approval added the following indications for pembrolizumab:
- Patients with metastatic NSCLC whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.
- Patients with metastatic NSCLC whose tumors express PD-L1 (TPS greater than or equal to 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
Approval was based on results of two randomized, controlled trials that demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) for patients randomized to pembrolizumab compared with chemotherapy.
In a trial of 305 patients who had no prior treatment for metastatic NSCLC and TPS greater than or equal to 50%, those who received pembrolizumab (200 mg every 3 weeks) had a significant improvement in PFS (HR 0.50 [95% CI: 0.37, 0.68]; p<0.001) with a median PFS of 10.3 months versus 6.0 months for those receiving platinum-based chemotherapy. A pre-specified interim analysis demonstrated a statistically significant improvement in OS for patients randomized to pembrolizumab as compared with chemotherapy (HR 0.60 [95% CI: 0.41, 0.89]; p<0.005).
In a three-arm trial of 1033 patients who were previously treated for metastatic NSCLC with a TPS greater than or equal to 1%, those randomized to pembrolizumab 2 mg/kg every 3 weeks (HR 0.71 (95% CI: 0.58, 0.88]; p<0.001) or pembrolizumab 10 mg/kg every 3 weeks (HR 0.61 [95% CI: 0.49, 0.75]; p<0.001) had an improved OS compared with patients receiving docetaxel. The median survival was 10.4 months in the pembrolizumab 2 mg/kg arm, 12.7 months in the pembrolizumab 10 mg/kg arm, and 8.5 months in the docetaxel arm.
The most common side effects of treatment with pembrolizumab included decreased appetite, fatigue, nausea, dyspnea, cough, and constipation. Rare but serious adverse events included immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
The recommended dose and schedule of pembrolizumab for NSCLC is 200 mg intravenously every three weeks.
FDA granted pembrolizumab breakthrough therapy designation and priority review status, and previously granted accelerated approval. The current approval converts the prior accelerated approval in second-line treatment of metastatic NSCLC patients to regular approval. The application for the first-line indication was approved nearly two months before the PDUFA goal date. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics
KEYTRUDA is a prescription medicine to treat a kind of skin cancer called melanoma. It may be used when your melanoma has spread or cannot be removed by surgery (advanced melanoma). It also is used to treat a kind of lung cancer called non-small cell lung cancer (NSCLC). KEYTRUDA may be used when your lung cancer has spread and tests positive for “PD-L1”* and you have tried chemotherapy that contains platinum, and it did not work or is no longer working and if your tumor has an abnormal “EGFR” or “ALK” gene,* and you have also tried an EGFR or ALK inhibitor medicine. It also is used to treat a kind of cancer called head and neck squamous cell cancer (HNSCC). KEYTRUDA may be used when your HNSCC has returned or spread and you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
It is not known if KEYTRUDA is safe and effective in children less than 18 years of age.
PD-L1 = programmed death ligand 1; EGFR = epidermal growth factor receptor; ALK = anaplastic lymphoma kinase.
Important Risk Information About KEYTRUDA® (pembrolizumab)
KEYTRUDA is a medicine that may treat your melanoma or lung cancer or head and neck cancer by working with your immune system. KEYTRUDA can cause your immune system to attack normal organs and tissues in many areas of your body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.
Call or see your doctor right away if you develop any symptoms of the following problems or these symptoms get worse:
Lung problems (pneumonitis). Symptoms of pneumonitis may include shortness of breath, chest pain, or new or worse cough.
Intestinal problems (colitis) that can lead to tears or holes in your intestine. Signs and symptoms of colitis may include diarrhea or more bowel movements than usual, stools that are black, tarry, sticky, or have blood or mucus; or severe stomach-area (abdomen) pain or tenderness.
Liver problems (hepatitis). Signs and symptoms of hepatitis may include yellowing of your skin or the whites of your eyes, nausea or vomiting, pain on the right side of your stomach area (abdomen), dark urine, feeling less hungry than usual, or bleeding or bruising more easily than normal.
Hormone gland problems (especially the thyroid, pituitary, adrenal glands, and pancreas). Signs and symptoms that your hormone glands are not working properly may include rapid heart beat, weight loss or weight gain, increased sweating, feeling more hungry or thirsty, urinating more often than usual, hair loss, feeling cold, constipation, your voice gets deeper, muscle aches, dizziness or fainting, or headaches that will not go away or unusual headache.
Kidney problems, including nephritis and kidney failure. Signs of kidney problems may include change in the amount or color of your urine.
Problems in other organs. Signs of these problems may include rash, changes in eyesight, severe or persistent muscle or joint pains, severe muscle weakness, or low red blood cells (anemia).
Infusion (IV) reactions, that can sometimes be severe and life-threatening. Signs and symptoms of infusion reactions may include chills or shaking, shortness of breath or wheezing, itching or rash, flushing, dizziness, fever, or feeling like passing out.
Getting medical treatment right away may help keep these problems from becoming more serious. Your doctor will check you for these problems during treatment with KEYTRUDA. Your doctor may treat you with corticosteroid or hormone replacement medicines. Your doctor may also need to delay or completely stop treatment with KEYTRUDA if you have severe side effects.
Before you receive KEYTRUDA, tell your doctor if you have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus; have had an organ transplant; have lung or breathing problems; have liver problems; or have any other medical problems.
If you are pregnant or plan to become pregnant, tell your doctor. KEYTRUDA can harm your unborn baby. Females who are able to become pregnant should use an effective method of birth control during treatment and for at least 4 months after the final dose of KEYTRUDA. Tell your doctor right away if you become pregnant during treatment with KEYTRUDA.
If you are breastfeeding or plan to breastfeed, tell your doctor. It is not known if KEYTRUDA passes into your breast milk. Do not breastfeed during treatment with KEYTRUDA and for 4 months after your final dose of KEYTRUDA.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Common side effects in people who received KEYTRUDA include feeling tired, decreased appetite, and shortness of breath.
Other common side effects in people with melanoma include itching, rash, constipation, diarrhea, and nausea.
Other common side effects in people with NSCLC include cough.
These are not all the possible side effects of KEYTRUDA. Tell your doctor if you have any side effect that bothers you or that does not go away. For more information, ask your doctor or pharmacist.