Why a New Immunotherapy for Lung Cancer Works for Only Some People

Cancer genomics researcher Timothy Chan

Genomics researcher Timothy Chan was surprised to discover that lung tumors with a lot of smoking-induced mutations tend to respond better to anti-PD-1 immunotherapy.

When the US Food and Drug Administration approved the drug nivolumab (Opdivo®) last month for use in patients with advanced non-small cell lung cancer (NSCLC), it marked yet another milestone for a new generation of cancer therapies that unleash the immune system to destroy cancer cells.

The drug — called a PD-1 inhibitor — removes a natural brake on the immune system. Memorial Sloan Kettering physician-scientists played a major role in developing this approach, which is producing impressive results when combined with standard anticancer therapies. The effectiveness of the PD-1 inhibitor against lung cancer is especially promising, as the disease is very common and urgently needs better treatments.

The therapy has produced remarkable results, completely eliminating metastatic cancer in some patients. But PD-1 inhibitors are effective in only 20 to 30 percent of people with NSCLC — and so far doctors haven’t been able to predict which patients are most likely to benefit.

Now researchers have gained clarity about what type of tumors this treatment tends to work against. In studying DNA changes in tumors of NSCLC patients who received pembrolizumab, another PD-1 inhibitor, MSK scientists identified a genetic pattern that correlates with successful treatment. This pattern is characteristic of tumors that contain a lot of mutations caused by smoking.

For the first time, a mutational pattern has been linked to immunotherapy outcome.

The findings, published in the April 3 issue of the journal Science, could guide the use of PD-1 inhibitors in lung cancer patients and also influence clinical trial approaches to investigate the drugs for other cancer types.

“The link between smoking-related mutations and immunotherapy responsiveness was totally unexpected,” says MSK cancer scientist Timothy Chan, who led the research. “And this is the first time anyone has shown that a widespread mutational landscape clearly affects the outcome of an immunotherapy.”

The landscape of mutations Dr. Chan describes is typical of cells whose DNA has been damaged by exposure to certain chemicals — including those present in cigarette smoke — or radiation. The damage often leads to a type of genetic error called transversion.

Dr. Chan and his colleagues, including medical oncologist Matthew Hellmann who specializes in lung cancer and is a co-first author on the paper, performed a thorough DNA sequencing analysis of tumors from 34 NSCLC patients who had been treated with pembrolizumab, which is presently being used for melanoma treatment and studied in clinical trials for lung cancer and several other cancers. They discovered that patients are more likely to respond to the therapy if their tumor DNA displays a high number of transversions, a characteristic feature of smoking-related cancers.

Among patients whose tumors had this genetic signature, 72 percent had a lasting benefit from the treatment that continued for six months or more. In comparison, these responses happened in only 13 percent of people whose tumors had low transversion numbers.

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A Genomic Test to Guide Treatment

While results indicate that both smokers and nonsmokers with NSCLC may benefit from anti-PD-1 immunotherapy, smokers are much more likely to respond. “It’s relatively easy to find out whether a patient has the ‘smoking signature’ by sequencing their tumor DNA,” Dr. Chan says.

“Interestingly,” he adds, “we found that performing the genomic test was a much better way of identifying responders than collecting data about the patients’ smoking history.” This may be because susceptibility to tobacco exposure varies among people, and patients with similar smoking histories may not have the same amount of mutations in their tumor DNA.

Genetic testing could help doctors and patients make better-informed choices about whether to pursue anti-PD-1 therapy for NSCLC. This means patients with disease that isn’t treatable with immunotherapy could be spared from getting the drug and suffering from its side effects, which often are mild but in some cases can be serious or even life threatening.

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Implications for a Range of Cancers

The impact of the findings extends well beyond NSCLC patients with this specific mutational profile. Smoking can lead to many types of cancer other than lung, including head and neck, bladder, and esophageal cancer. “All these smoking-related cancers have a similar mutational landscape,” Dr. Chan explains. He posits that any cancer, regardless of where in the body it first arises, is more likely to be sensitive to the drug if it carries the genetic signature.

Presently, researchers are launching clinical trials of PD-1 inhibitors in a range of cancer types, hoping to figure out why some people respond and others don’t. “Based on our data,” Dr. Chan says, “there may be a rationale for testing these drugs primarily in patients whose tumors have a high transversion rate” and hence may have a better chance of responding.

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New Insights about How Checkpoint Inhibitors Work

In November, Dr. Chan and his colleagues reported on findings that explain why another immunotherapy drug, ipilimumab (Yervoy®), works for only about one in five patients with advanced melanoma. A conclusion from that study is that the more mutations a tumor has, the more likely it is to respond to drugs known as checkpoint inhibitors, such as ipilimumab, nivolumab, and pembrolizumab.

In particular, the presence of mutations that make cancer cells express new antigens — substances that the immune system is able to “see” and trigger a response against — appears to be linked to immunotherapy responsiveness.

The new lung cancer study supports this hypothesis. Transversions often lead to changes in a cell’s genetic code, which in some cases may result in the production of new antigens. One explanation as to why lung tumors with high transversion numbers might be more sensitive to a checkpoint inhibitor could be that they are easier for the immune system to detect.

Some features of immunotherapy responsiveness may apply to various cancers.

“It is very important to see that the initial observations we made regarding mutations and immunotherapy response in melanoma are also applicable to other cancers,” notes physician-scientist Jedd Wolchok, a leading immunotherapy expert and a co-author of the study. “This reinforces our belief that there are common features of the relationship between the immune system and various cancers.”

The researchers are hopeful these insights will make it possible to achieve even better results for more patients with different cancer types. Dr. Chan notes that scientists are only beginning to understand the relationship between a tumor’s genetic makeup and its responsiveness to checkpoint inhibitors. Future studies might reveal whether gene changes induced by factors other than smoking, such as UV light or aging, contribute to shaping a tumor’s responsiveness to immunotherapy.

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Angela, we’re sorry to hear about your husband’s diagnosis. We recommend you discuss treatment options with his healthcare team, because we are not able to offer treatment advice on our blog. If he’d like to come to MSK for treatment or a second opinion, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.

Do you have any information on Opdivo and high grade serous epith ovarian cancer. I know there are some clin trials. My wife (3c) has been under treatment with various drugs for almost 3.5 years and has never had a remission lasting more then 7 months which was right after front line treatment and debulking. I have heard that some places are showing that it has shrunk the solid tumors.
What has MSK's experience been and does a mutation need be present to potentially obtain a response.
I have also heard of pseudo progression and wondered if patients do worse for awhile with progression of disease and in this case, elevation of ca125. Of course a CT will actually be more factual. Thank you.

William, we sent your questions to Alexandra Snyder Charen, an expert in using immunotherapy for treating gynecologic cancers, and this was her response: “There have been 3 studies presented or published on PD(L)1 blockade in ovarian cancers: Disis and colleagues and Varga and colleagues at ASCO 2015, and Hamanishi and colleagues at ASCO 2014 as well as the same study, published in the Journal of Clinic Oncology (https://www.ncbi.nlm.nih.gov/pubmed/26351349). In part as a result of these promising results, there are ongoing studies of Opdivo (nivolumab) as well as other checkpoint blockade inhibitors in high-grade serous (epithelial) ovarian cancer. MSK is leading or participating in several of these; the studies are all still too recent to know for certain how safe and effective the drugs and combinations are in patients with ovarian cancer. William is correct that pseudoprogression has occurred across disease types, and that the significance of CA125 as a marker in patients on immunotherapy remains to be firmly determined. We would welcome his wife for consideration for one of our studies if she is interested.”

If you’d like to learn more about making an appointment here, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment, and best wishes to you and your wife.

My mom has stage 4 lung cancer she had radiation in the past on the same lung where the cancer is so that was not an option this time . The cancer is almost blocking her right lung and she also has a small spot in the left lung . The doctor is now giving her Opdivo but she still continues to smoke ...with her still smoking will Opdivo do anything ?

Dear Alley,
We forwarded your question to Matthew Hellmann, a lung cancer doctor at MSK, who said: “I would certainly encourage anyone to quit smoking, even after the diagnosis of lung cancer. Smoking may decrease the effectiveness of chemotherapy and may increase the risk of inflammation in the lungs associated with medicines like Opdivo. Still, Opdivo can work in patients who are smoking so it is reasonable to follow your doctor’s advice with continuing this treatment…. while continuing to support and encourage her to quit smoking.” Thank you for your comment.

My father has SCLC. He has undergone 9 chemo treatments over the past year which have worked on shrinking the tumors. The tumor In the liver has grown significantly .. He has started opdivo ...first treatment 5 days ago..
Time does not appear to be on our side and I am wondering generally how long does it take for opdivo to kick in ? He has 2nd treatment scheduled in 9 days . He looked so jaundice yesterday ... We are praying for a miracle .. Just curious about time frame of when drug kicks in .. Thank you Robin

Hi Robin, we are very sorry to hear your father is going through this. Because all cases are different, we recommend you discuss these questions with your father’s healthcare team. Thank you for your comment and best wishes to your family.

Hello, I am interested in the possibility that Opdivo seems to work better on people with a smoking history. I was first diagnosed with squamous NSCLC in november 2013. I immediately gave up smoking and have never smoked since. I was mmediately treated with radical radio-chemotherapy. Up until February 2016 I was doing well, scans showed scar tissue but not tests showed active cancer. So I was haeding towards that magic '5 year' mark. Then in February 2016 I was diagnosed by CT scan to have numerous metastastses to the liver and my CEA level was up over 1500. I was immediately put on a standard regime of Gemcitabine plus Carbopaltin. Initial results were almost miraculous. My lasts scan (two months ago) showed only 2 (visible) lesions, both about 18mm. BUT....my CEA level has now started to climb, from 14 to 35 (as at 26 Sep 2016). My oncologist is talking about going on to Opdivo. After all of this history, my question is - and I accept that it is probably a really stupid one - is there any indication that Opdivo works better on current smokers than ex-smokers? The crazy part of this is that I am asking wheter I should take up smaoking again, to improve my chances of Opdivo working! I have not had any genetic tests done. Maybe the question isn't as stupid as it sounds, but thanks for any advice you can give. Regards, Geoff Ingram (Melbourne Australia)

Dear Geoffrey,
We forwarded your question to Matthew Hellmann, a lung cancer and immunotherapy expert at MSK, and here is what he said: “NO! You should NOT start smoking again. There is no evidence that current smokers have better response (may have worse response and increased risk of side effects like pneumonitis) to PD1 therapy.”

Absolutely phenomenal,site. Information valuable, easily understandable and to a degree, re-assuring 3

Dear Arnold, we are glad to know you have found the information presented in our site helpful. Thank you for sharing your thoughts on our blog.

My sister-in-law has EGFR+ nsclc and has been through tarceva, tagrisso, chemo and will be starting Opdivo this week. I am aware of the study showing the combination of Opdivo and Yervoy to be superior to Opdivo alone as first line therapy. Have there been any cases where the combo has been used after treatment failure? Are you aware of any way a patient might be able to get Yervoy added to their regimen? Do oncologists ever use off-label treatments outside of a clinical trial? Thank you.

Dear Claire,
We aren’t aware of a trial that looked at the combination of Opdivo and Yervoy in recurrent, previously treated NSCLC. There was, however, a study that looked at a similar drug, Keytruda (pembrolizumab), and Yervoy: http://meetinglibrary.asco.org/content/167103-176
We recommend that your sister-in-law talk to her doctor about what clinical trials and therapy options might be available to her, given her prior therapies.

Are transpant patients on Tacrolimus eligible for trials

Dear Ernest, every clinical trial has it’s own set of eligibility requirements. To learn more about how to participate in a clinical trial or view a listing of open trials at MSK, please visit: https://www.mskcc.org/cancer-care/clinical-trials. If you have any questions about your eligibility to participate in any of these studies or would like to make an appointment with one of our specialists to discuss possible treatment options, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

I want to ask if there are patients with a complete response to the drug pembrolizumab for smokers who has stage 4 non small lung cancer? and they were cured completely as second line treatment

Dear Bernard, there are cases of people with advanced NSCLC who have done very well on pembrolizumab, experiencing durable, complete responses. Whether these responses are truly “cures” is hard to say, given that the treatment is relatively new. Unfortunately, it is currently not possible to predict who will respond and who will not, although former smokers tend to have a slightly higher overall response rate.

Thank you for reaching out to us.

even with PDL 1 negative? My Father has the PDL1 negative (non small squamous lung cancer) . is there any patient with his case who take the pembrolizumab or Yervoy is better in the case of negative PDL 1 ?

Dear Bernard, it’s best if you consult with your father’s oncologist to answer specific questions about his care. If you would like to make an appointment with one of our specialists to discuss possible treatment options or a second opinion, please call our Physician Referral Service at 800-525-2225. Thanks again for reaching out to us.

Thank you for the info, but the question is about the results obtained in the trial which have showed the better results for the smokers . ALL the patients participated had PDL 1 positive?

Bernard, the role of a person’s PD-L1 status in influencing response to treatment is still an ongoing area of research. While people with higher levels of PD-L1 positivity tend to have higher response rates overall, even some people with no or little PD-L1 positivity can also respond—sometimes very well. This may be because PD-L1 is a “dynamic biomarker” and can change over time. Doctors are also exploring ways to increase someone’s PD-L1 positivity with the use of other immune-stimulating drugs. We recommend you talk to your father’s physician for more information about what treatments he is eligible for given his PD-L1 status.

My husband (heavy smoker) was diagnosed with NSCLC in Aug of 2015, had carboplatin chemo and radiation treatments, recently started OPDIVO. How long does it take for OPDIVO treatment to start working (2 cycles, 4... or a few months)?

Dear Marie, we are sorry to hear about your husband’s diagnosis. Everyone’s response to treatment is unique, so it’s hard to answer that without knowing more about him and his disease. We recommend you discuss this with his oncologist. Thank you for reaching out to us.

I was diagnosed with lung cancer Dec. 2015. They removed the lower part of my left lung & I underwent chemo & radiation. At the 3 month check up all tests came back negative for cancer. Now Dec 2016 they have found tiny pin holes in my bones & say it is cancer. The dr is sending out for PDL results. What happens now?

Dear Debbie, we are sorry to hear about your diagnosis. We can’t answer your question without knowing more about you and your cancer. If you would like to make an appointment with one of our specialists to discuss possible next steps in your care, please call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

My husband was diagnosed with stage 2 of NSCLC in august of 2015. Since then he had chemo, radiation which did not do to much. Six months after radiation he has received 2 cycles of OPDIVO. When do you know that OPDIVO started to work, after how many treatments (or after how many months)?

Dear Marie, we are sorry to hear about your husband’s diagnosis. It’s difficult to predict an individual’s response to any particular therapy because everyone’s experience is unique. We recommend that you follow-up with his oncologist, who is better-equipped to offer more information about his prognosis based on his particular circumstances. Thank you for reaching out to us.

My father is currently undergoing immunotherapy for stage 4 NSC lung cancer. He has shown some decrease in his tumors over the course of his 6 month treatment. One major side effect has been an eruption of serious squamous cell skin cancers on his legs/arms (at least a dozen). They are quite large, and requiring extensive MOHS surgery to repair. Our doctor has not seen skin cancer as a side effect of the immunotherapy (nivolumab plus ipilimumab) previously. thoughts if this is a side effect?

Dear Lisa, we’re sorry to hear your father is going through this. We checked with Matthew Hellmann, who is an expert in immunotherapy for lung cancer, and he said that this is not a known side effect. We recommend you discuss this further with your father’s doctor. Thank you for your comment.

I was diagnosed with Stage IV NSCLC with metastasis to the brain. Stereotactic brain surgery successfully eradicated the brain lesions, followed by aggressive chemo for the lung. The chemo failed to stop metastasis to the liver and hip bones, so it was found to have failed.
Switched to Opdivo and after 5 infusions CT scan revealed liver lesion doubled in size and thoracic lymph nodes did too. Primary tumor size did not change.
Could this be pseudo progression?
My doctor deemed Opdivo to have failed and has recommended I move on to clinical trial. Just wondering what you think.

Dear JR, we are sorry to hear about your diagnosis. If you would like to consult with one of our specialists about possible next steps in your care, please call our Physician Referral Service to make an appointment. The number is 800-525-2225. Thank you for reaching out to us.

My father had first infusion of opdivo last monday (squamous NS lung cancer) he felt with pain in the place of tumor in the shoulders . Is there means that the drug works ? and what s the medicament for this pain? 30 mg Morphine does not make him better?

Dear Bernard, we’re sorry to hear that your father is experiencing pain with his treatment. We recommend that he discuss this with his healthcare team. Thank you for your comment.

My husband has been diagnosed with atypical carcinoid tumor after VATS was done to take out the nodule and do a biopsy. Is there presently a cure / treatment , immunotherapy , genetic profiling for this type of tumor at mskcc. Our onco said its a rare form of carcinoid. Would appreciate any advise.

Dear Ginger, we’re very sorry to hear about your husband’s diagnosis. MSK has a number of experts in treating carcinoid tumors. If your husband would like to arrange for a consultation here, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment and best wishes to you.

My father has stage 4 SCLC and is currently in a trial treatment thought Sloan Kettering . Things were going very well for him and then suddenly he took a turn for the worst. After being int eh hospital for 2 weeks they figured out that his immune system was fighting itself. He is still in the Hospital , and the next step is a Rehab due to the fact that he will now have to learn how to walk again. They are still having issues regulating his blood pressure because it keeps dropping very low. The question is can he ever return to immunotherapy treatment? Or will this happen again? Is this the end of our options as far as cancer treatment?
Thank you for your guidance
Mehgen R.

Dear Mehgen, we’re so sorry to hear that your father is going through this. We recommend that you discuss your questions and concerns with his MSK healthcare team, because they are familiar with his case. Thank you for your comment and best wishes to you and your family.

Opdivo was working great for me for over five months. It seemed to actually be shrinking the tumors then I developed pnueminitus. Is there any research into a refinement of the drug or something besides prednisone to treat pneuminitis so that I could continue immunotherapy.

Dear Darrell, we’re sorry to hear you experienced this complication. We recommend you discuss this with your healthcare team. Thank you for your comment, and best wishes to you.

I was diagnosed with Stage IIIB NSCLC in May 2015. I went through chemo and radiation. It had spread to two lymph nodes by my neck. Recently I had CT and it looks like my tumor might be growing. It is 24 mm. My pet scan is scheduled for August 1. If it has come back, would they be able to do immunotherapy on me? Should I start smoking again if the treatment works better on smoking. I am getting a new Fellow for my doctor. I go to the VA. I wish they had educational classes on this.

Dear Jackie, we’re sorry to hear about your diagnosis. If you’re interested in having a consultation with an expert at MSK about treatment options, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment.

Our experts definitely do not recommend starting smoking again. Smoking can have many negative effects on your health. In addition, the mutations that result from smoking and may make this therapy more effective take many, many years to develop. Thank you for your comment, and best wishes to you.

82 yr old mediastinal tumor SCLC - 35 radiation re and 3 sessions off chemo - completed Rx in Dec 2013 - no sign of recurrence till Jan 2017 - lymph node hilar region positive for SCLC. What treatments are recommended ? Immunotherapy?
Any current clinical trials?

After Carboplatinum/Alimta treatment (which worked for several months), and then Gemzar (which was totally ineffective), I have had three Opdivo treatments, which a PET Scan has shown may be proving effective. Unfortunately I have developed a serious case of anemia (hemoglobin 7.8). The doctors are trying to rule out other causes, but the Opdivo seems to be a likely suspect. I know you can't comment on my specific case, but in general is it possible to treat immunotherapy-induced anemia and continue the immunotherapy?

Dear Joanne, we’re very sorry to hear that you’re going through this. We recommend that you discuss your options for treatment with your medical team. If you would like to have a consultation with experts at MSK, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment, and best wishes to you.


I have a family member, 46yo Korean female (non-smoker) who has stage IV non-small cell lung cancer (mets to brain and bones) - adenocarcinoma with alk mutation. She's been diagnosed about 3-4 years ago and disease have been stable on alk inhibitors. But now she's on her 3rd or 4rth Alk inhibitor with progression. Is there any clinical trial that she could enroll in involving immunotherapy combined with chemotherapy or any other promising therapy in the horizon for those who become resistant to alk inhibitors?

Dear Kyung, we’re sorry to hear about your family member’s diagnosis. If she would like to come to MSK for a consultation, she can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment, and best wishes to you and your family.

I am a 35 year old women with stage 4 carcinoid lung cancer the doctor told me she didn't know if she could save my life because it's growing at a rate of 25 percent. What can you tell me about my kind of cancer and immunotherapy?

We’re very sorry to hear about your diagnosis. If you would like to come to MSK for treatment or a second opinion, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. If you are not in the NYC area and not able to travel here, we recommend that you seek out a consultation at a National Cancer Institute-designated cancer center that is closer to where you live. You can find a list here: https://www.cancer.gov/research/nci-role/cancer-centers

Thank you for your comment, and best wishes to you.

I have been treated with Lupron and Xtandi for my prostate cancer which has held it in check to 3years. Now a recent chest x-ray shows two places that,after needle biopsy's of my lungs shows they are cancer. I am having cyber knife radiation sesseions on the two spots and the Dr. now wants me to take Optivo to block small possible cancer cells in both lungs. Is this a good idea? Grady