Medical Oncology
Five years after starting pembrolizumab for metastatic lung cancer, 31.9 percent of patients were alive. With chemotherapy the figure was 16.3 percent.
That result, from the first immunotherapy trial to reach five years of follow-up, applied to patients whose tumors carried a high level of one protein, PD-L1. Pembrolizumab does not attack the cancer. It releases the immune system to do so, and the same drug now treats melanoma, bowel, bladder, kidney, cervical, head and neck, stomach and breast cancers in defined situations, with tests that decide who will gain from it. Send us your pathology report, your PD-L1 and molecular results and your scans, and a medical oncologist will tell you whether pembrolizumab is your treatment and how a course is arranged between Istanbul and home.
31.9% vs 16.3%
Five-year survival, metastatic lung cancer, PD-L1 high
16.5 vs 8.2
Months without progression, MSI-high bowel cancer
30 minutes
Infusion time, every three or six weeks
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Oncologist's review of your pathology and scans
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Tests decide.
Pembrolizumab helps a minority of patients enormously and the rest little, and three tests on the tumor sort one group from the other. The first measures PD-L1 on the cancer cells, reported as the tumor proportion score or the combined positive score, and in lung cancer a score of 50 percent or more marks the patients who can be treated with pembrolizumab alone. The second looks for microsatellite instability, or mismatch repair deficiency, a defect in the tumor's DNA repair that fills it with mutations and makes it visible to T cells. Tumors with that defect respond to pembrolizumab wherever in the body they arise.
The third counts mutations directly, the tumor mutational burden, and a high count has the same effect. Alongside those, tests for the driver mutations that have their own drugs, EGFR and ALK above all in lung cancer, decide who should receive a targeted tablet in its place.
Which cancers does pembrolizumab treat, and what did the trials find?
Lung cancer
Non-small-cell lung cancer is where the evidence is deepest. KEYNOTE-024 randomized 305 patients with metastatic disease, a PD-L1 score of at least 50 percent and no EGFR or ALK mutation to pembrolizumab alone or to platinum chemotherapy. Median survival was 26.3 months against 13.4, five-year survival 31.9 against 16.3 percent, and of the 39 patients who completed the full two years of the drug, 82 percent were alive at five years. For patients whose PD-L1 score is lower, KEYNOTE-189 added pembrolizumab to chemotherapy in 616 patients with non-squamous disease. Survival at one year was 69.2 percent with the combination and 49.4 percent with chemotherapy alone, across every level of PD-L1. Pembrolizumab therefore serves the whole of metastatic non-small-cell lung cancer without a driver mutation, alone where PD-L1 is high and with chemotherapy where it is not, and it is also given for a year after surgery or after chemoradiation in earlier stages.
Melanoma
The trial that made pembrolizumab a household name. KEYNOTE-006 randomized 834 patients with advanced melanoma to pembrolizumab or to the older immunotherapy ipilimumab. One-year survival was 74.1 percent against 58.2, the response rate 33 against 12 percent, and serious side effects were less frequent with pembrolizumab. Surgery-treated high-risk melanoma now gets it too, for a year.
Bowel cancer with mismatch repair deficiency
About one bowel cancer in twenty carries the DNA repair defect. KEYNOTE-177 randomized 307 patients with such tumors, already metastatic, to pembrolizumab or to chemotherapy as first treatment. The time before the disease progressed doubled, 16.5 months against 8.2, and serious treatment-related side effects fell from 66 to 22 percent. Chemotherapy was removed from the first line for these patients as a result.
Head and neck, bladder, kidney, cervix, stomach, esophagus, breast, endometrium
Each has its own trials and its own test. Head and neck cancers are treated by PD-L1 combined positive score, bladder and kidney cancers in combination with other drugs, cervical cancer with chemoradiation or chemotherapy by PD-L1 score, and triple-negative breast cancer before surgery. Endometrial and other cancers with the mismatch repair defect are treated on that basis alone. The reply to your file states the trial that applies to your cancer and the test it requires.
Where pembrolizumab is the wrong drug
Lung cancers with an EGFR, ALK or other driver mutation respond to targeted tablets and poorly to immunotherapy, and giving pembrolizumab first can make the tablets more toxic afterward, so the mutation tests come before any decision. Cancers with a PD-L1 score of zero and no mismatch repair defect gain little from pembrolizumab alone. Patients with an active autoimmune disease, a transplanted organ or a need for high-dose steroids can be harmed by it, and each case is weighed individually.
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Trials behind the main uses
| Cancer |
Trial |
Compared |
Result |
| Lung, PD-L1 at least 50 percent |
KEYNOTE-024, 305 patients, five-year report in the Journal of Clinical Oncology 2021 |
Pembrolizumab alone against chemotherapy |
Median survival 26.3 against 13.4 months. Five-year survival 31.9 against 16.3 percent |
| Lung, any PD-L1, non-squamous |
KEYNOTE-189, 616 patients, New England Journal of Medicine 2018 |
Chemotherapy with pembrolizumab or placebo |
One-year survival 69.2 against 49.4 percent. Benefit at every PD-L1 level |
| Melanoma |
KEYNOTE-006, 834 patients, New England Journal of Medicine 2015 |
Pembrolizumab against ipilimumab |
One-year survival 74.1 against 58.2 percent. Fewer serious side effects |
| Bowel, mismatch repair deficient |
KEYNOTE-177, 307 patients, New England Journal of Medicine 2020 |
Pembrolizumab against chemotherapy |
Progression-free survival 16.5 against 8.2 months. Serious side effects 22 against 66 percent |
How is a course given, and how long does it last?
- Baseline. Blood tests for thyroid, liver, kidney, blood sugar and blood count, a test for hepatitis B and C, and the scans that will serve as the comparison. A cannula or, for a long course, a port under the skin.
- The infusion. 200 milligrams into a vein over 30 minutes every three weeks, or 400 milligrams every six weeks. There is no hair loss and no need for anti-sickness drugs beforehand. You go home the same day.
- Before each dose. Blood tests and a symptom check by the oncology nurse, since most side effects are caught in the blood or in the questions before they are felt.
- Every nine to twelve weeks. A CT or PET-CT to measure the response. A tumor that grows on the first scan and shrinks on the second is a known pattern, and the decision to stop is made on the trend and on how you feel, never on one scan.
- The end. Two years, 35 cycles, for metastatic disease that keeps responding, one year after surgery or chemoradiation, or earlier if the disease progresses or a side effect makes it unsafe.
Alone, or with chemotherapy
Alone is possible. A high PD-L1 score in lung cancer, or a mismatch repair defect in any cancer, allows pembrolizumab by itself, which spares the patient chemotherapy entirely. A lower score means the drug is combined with chemotherapy for the first four cycles and then continued alone, as in KEYNOTE-189, or combined with other immunotherapy or targeted drugs in kidney, bladder and head and neck cancers. The combination brings the side effects of both, and the reply to your file names the regimen and the reason for it.
How long the benefit lasts
Durability sets immunotherapy apart. In KEYNOTE-024, 82 percent of the patients who finished two years of pembrolizumab were alive three years later, and in KEYNOTE-006 responses to melanoma were ongoing in most responders at the time of the report. That does not mean everyone responds. Between a third and a half of patients selected by the tests do, and for the others the disease progresses within months and the plan changes.
What are the side effects?
An immune system released against a tumor can turn on any healthy organ. The resulting problems are called immune-related adverse events, and they differ from chemotherapy side effects in three ways. Timing first. They can appear at any moment, including months after the last dose. Steroids treat them, by suppressing the immune system, and waiting makes them worse. Most are mild and reversible. A few are dangerous when missed.
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Immune-related side effects, by organ
| Organ |
How it shows |
How often |
What is done |
| Skin |
Rash, itching, patches of lost pigment |
Common, mostly mild |
Creams, antihistamines, steroids for severe rash |
| Thyroid |
Tiredness, weight change, feeling cold or hot, found on the routine blood test |
Common, about one patient in ten |
Thyroid tablets for life if the gland fails. The drug continues |
| Bowel |
Diarrhea, abdominal pain, blood in the stool |
A few percent, more with combinations |
Steroids, and a stronger immune suppressant if they fail. Untreated, it can perforate |
| Liver |
Rising liver enzymes on the blood test, rarely jaundice |
A few percent |
Steroids, and the drug is paused or stopped |
| Lung |
New cough, breathlessness, chest pain |
Under five percent, more in lung cancer |
Steroids and admission. The most dangerous common event |
| Hormone glands |
Severe tiredness, headache, low blood pressure, low sugar |
Rare |
Hormone replacement, sometimes for life |
| Heart, nerves, kidneys, joints, eyes |
Chest pain, weakness, numbness, joint pain, blurred vision |
Rare, heart under one percent |
Admission, steroids, specialist care. Heart inflammation can be fatal |
What to do when something changes
- Report any new symptom to the oncology team the same day, however small. A mild problem caught early stays mild.
- Never take steroids, stop the drug or restart it on your own. The guideline from the American Society of Clinical Oncology sets out, organ by organ, when the drug continues, pauses or stops.
- Carry a card stating that you are on immunotherapy, because a doctor who does not know may treat diarrhea as an infection and pneumonitis as pneumonia.
- Keep every blood test appointment. The thyroid, the liver and the sugar are watched in the blood before they cause symptoms.
Go to a hospital the same day
Breathlessness or a new cough. Diarrhea more than four times a day or with blood. Severe headache with tiredness or fainting. Chest pain, palpitations or swollen legs. Yellow eyes. Weakness or numbness spreading. Confusion. A rash that blisters or involves the mouth. Tell them you are on pembrolizumab.
Who needs extra care
The ASCO guideline was written because the side effects follow no chemotherapy pattern and a general physician may not recognize them. In general it keeps the drug going with close watching for grade 1 events, pauses it for grade 2 until they settle, and for grade 3 or 4 gives high-dose steroids and stops the drug, permanently for some organs. Patients with a pre-existing autoimmune disease are treatable, with the disease's own specialist involved and the risk of a flare accepted in advance. Patients on steroids for another reason, patients with a transplanted organ and patients with prior severe immune events from a related drug are the cases where the decision is hardest, and the reply to a file that mentions any of these will say so plainly.
Who it suits, and how a course is arranged from abroad
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Pembrolizumab from abroad, situation by situation
| Your situation |
What fits |
| Newly diagnosed, treatment not yet started |
Come for the full work-up. PD-L1, mismatch repair and driver mutation testing on the biopsy, staging scans, tumor board, and the first cycle here, with the regimen written for continuation at home. |
| Already on pembrolizumab at home |
A second opinion on the plan, with the scans and tests reviewed. Continuation here is possible and seldom sensible, since the drug is the same everywhere and the value lies in the team that watches for side effects. |
| Pembrolizumab not available or unaffordable at home |
A course here, with cycles every three or six weeks, hotel between cycles or return trips, and blood tests done at home between visits where a laboratory can be trusted. |
| Disease progressing on pembrolizumab |
Review of what comes next, which depends on the cancer, and access to the trials and the drugs the tumor board can offer. |
| Told you are not a candidate |
A review of the tests that led to that verdict. PD-L1 scoring varies between laboratories, and mismatch repair testing is sometimes never done. |
- The pathology report, and the PD-L1, mismatch repair, tumor mutational burden and driver mutation results if they exist. If they do not, say so, because the biopsy blocks can be tested here.
- The staging scans with images, and a brain MRI for lung cancer and melanoma.
- Every cancer treatment so far, with dates and response.
- Blood tests, including thyroid, liver, kidney and hepatitis serology.
- Any autoimmune disease, transplant or long-term steroid use, and every medicine you take.
What decides the cost
Price follows the drug.
Every quote counts it cycle by cycle. A 200-milligram dose every three weeks and a 400-milligram dose every six weeks cost the same per month, so the six-weekly schedule halves the number of visits without changing the drug bill. Chemotherapy or a second immunotherapy given alongside adds its own drug cost and day-unit time. The tests that decide eligibility, PD-L1 immunohistochemistry, mismatch repair and a molecular panel, are separate items when the biopsy has to be tested here, and so are the staging scans and the scans every nine to twelve weeks.
Blood tests before each cycle, a port, and any admission for an immune side effect are charged as they arise, and a course of steroids for a serious event sometimes means a week in hospital. Cycle count is the largest unknown. A responder may receive 35. A non-responder, four. Packages published by hospitals in Istanbul for pembrolizumab quote a price per cycle, sometimes with the first cycle bundled with a PET-CT, a brain MRI and blood tests, and they leave the hotel and the follow-up scans outside.
Compare per cycle. Ask whether the eligibility tests are included. Ask what an admission for a side effect would cost. Your own figure follows the free review of your file.
The trip, and care between cycles
One coordinator from the international patients team is assigned from your first message and stays with you for the whole course. The team works in English, Arabic, French, Russian, Serbian, Romanian and Spanish and arranges interpreting in other languages on request, and an interpreter attends the consultation, the tumor board feedback and every review. An invitation letter naming the hospital and the treating oncologist is sent about ten days before travel, and for a course of repeated visits a longer validity is requested. The international patients office arranges the airport transfer, the hotel for you and a companion, and the rides to the day unit. Nobody is admitted for the infusion itself. Rooms for anyone admitted have a companion bed. Halal, vegetarian and diabetic meals are available, a prayer room is on site, and a request for a female doctor is passed to the department and met wherever the rota allows.
Surgery, radiotherapy and medical oncology share one site, so a tumor board that combines pembrolizumab with an operation or a course of radiotherapy does not send you elsewhere.
Between cycles, most patients go home, so the length of stay in Istanbul is a few days per cycle.
A three-week or six-week interval allows a return to family and work, with the blood tests done at home a few days before the next cycle and sent to the coordinator, who stays reachable on the same WhatsApp number throughout. Fly whenever you like. Nothing in the course forbids it. Follow-up once you are back home is planned before you leave. A symptom that appears at home goes first to a local doctor with your immunotherapy card, and then to the coordinator, so that the oncologist here can advise on whether the next cycle goes ahead. Patients who cannot travel repeatedly stay in an apartment near the hospital for a block of cycles, and the six-weekly schedule makes that block shorter.
Pembrolizumab FAQ
How does pembrolizumab work?
It blocks PD-1, a brake on immune T cells that tumors exploit to switch them off. With the brake released, the immune system attacks the cancer. Responses can take weeks to appear and can last for years after the drug is stopped.
Who is eligible for Keytruda?
It depends on the cancer and on tests done on the tumor. In lung cancer a PD-L1 score of 50 percent or more allows pembrolizumab alone, and lower scores allow it with chemotherapy, provided there is no EGFR or ALK mutation. Cancers with a mismatch repair defect are eligible wherever they arise. Melanoma needs no test.
What is the success rate of pembrolizumab?
In metastatic lung cancer with high PD-L1, five-year survival was 31.9 percent against 16.3 with chemotherapy. In melanoma, one-year survival was 74 percent against 58, and in mismatch repair deficient bowel cancer the time before progression doubled. Between a third and a half of selected patients respond.
How often is pembrolizumab given, and for how long?
Every three weeks at 200 milligrams or every six weeks at 400, over 30 minutes, for up to two years in metastatic disease or one year after surgery or chemoradiation.
What are the side effects of Keytruda?
Immune reactions against healthy organs, above all the skin, thyroid, bowel, liver and lungs. Most are mild and treated with steroids. Rare ones affecting the heart, nerves or hormone glands are serious, and any new symptom is reported the same day.
Can I have my cycles at home between visits?
Yes, where the drug is available at home. The regimen is written for your own oncologist, blood tests are done locally, and the coordinator stays reachable. Many patients come for the work-up and the first cycle and continue at home.
