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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Commenting is disabled for this blog post.

I think we are all hoping for better widespread results.

May I suggest also a study of mesothelioma rumors which often are asbestos caused be made? To determine if asbestos has also made DNA changes and if so, would immunotherapy drugs work on meso cases.

Oscar, to learn about the link between asbestos and the DNA damage that leads to mesothelioma, you may find this article from the American Cancer Society useful: http://www.cancer.org/cancer/malignantmesothelioma/detailedguide/malign…

Memorial Sloan Kettering currently has one immunotherapy related trial for mesothelioma: http://www.mskcc.org/cancer-care/trial/10-134 (Vaccines are a type of immune therapy.)

We have another one planned that you can read more about here: http://www.mskcc.org/blog/immunotherapy-shows-promise-treating-solid-tu…

Thank you for your comment.

I would like to see a clinical trial for NSCLC squamous patients who have tumors with high transversion rates AND who have had some radiation therapy. Most of the trials have required standard chemo first with disease progression. Many stage III & 4 patients have very short life expectancies even with chemo. There are likely a large number of them who would be willing to sign up for PD-1 inhibitor trials and skip past the chemo.

Are there any clinical trials of nivolumab with other types of NSCLC, such as adenocarcinoma?

Dear David, the following clinical trial is evaluating nivolumab for people with adenocarcinoma at Memorial Sloan Kettering:

To make an appointment for a consultation with one of our specialists regarding this and other potential treatment options, please call our Physician Referral Service at 800-225-2225.

To search for other clinical trials at Memorial Sloan Kettering and elsewhere, visit www.clinicaltrials.gov.

Thank you for reaching out to us.
You may also be

My husband was diagnosed with stage 3a nsclc in February of 2014. He had 37 radiations and 4 rounds of chemo. He was a smoker and had quit 7 yrs prior to diagnosis. Chemo/radiation has destroyed his left lung and his tumor is about 60% of that lung. His esophagus was in field of radiation so he has a problem with water and has been the hospital for dehydration. I would love for him to be able to receive this type of treatment and it is available where we live. Some information that I have read wasn't very hopeful as extending his life using this treatment. It has metastasized into his right lymph node in his neck.

Hello...if it's known to be more responsive in smokers, why aren't more trials being done with SCLC which has a preponderance of smokers?

Tammie, thank you for reaching out. We do anticipate more clinical trials will be launched testing immunotherapy for SCLC. To learn about impending clinical trials for SCLC, you may contact Memorial Sloan Kettering’s Immunotherapeutics clinic at 646-888-3359.

In the meantime, you might contact the Cancer Research Institute at 1-855-216-0127 to learn about other immunotherapy clinical trials for SCLC.

Is any data available on the response of HPV caused lung cancer to PD-1?

Thank you for your question. We asked Dr. Chan, and he’s not aware of any data. He said he’ll let us know if he hears of anything. Thanks so much!

I have stage 4 metastic lung cancer lost 1/3 of lung last April now Dr. Say in lymph nodes and possible brain did MRI found spot on brain they say could be cancer I refused chemo and radiation. Looking for clinical trial in I'll.

Are there any immunotherapy trials available for my wife, a 71 year old former smoker with stage 4 small cell lung cancer? She has undergone chemo and radiation, with a recurrence of the cancer, but no signs of it spreading. She is otherwise in good health

Peter, we don’t currently have any immunotherapy trials for small cell lung cancer, but we have many other trials, including some testing targeted therapies. You can find the list at : https://www.mskcc.org/cancer-care/clinical-trials/search?keys=&disease=…

If your wife is interested in learning more, you can call our Physician Referral Service at 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.

wr are looking into immunotherapy my husband had a kidney transplant 10 years ago and the last 3 years he is fighting squamous cell carcinoma metastatic cancer . It started in his head moved to the lymphbodes and now lungs. We have done the DNA mutation study and did a clinical trial with targeted therapy . We have done chemo for 18 months . Our Dr has suggested immunotherapy has this had any success with transplant patient who were non smokers ? He did chew Tabacco in his 20-30's. We know there are risks involved but I have to find a way to keep my husband alive

My mom is stage 4 Non small cell adenocarcinoma. She is being treated at Roswell Cancer institute. It metastasized to her brain. The brain tumor was removed and she recorded radiation afterwards. Her lung cancer treatment consisted of 4 cisplatin and Altima treatments. The tumor grew 1cm now totaling 8cms. They are offering 10 rounds of radiation and then the nivolubam. I keep reading that chemo and nivo are done together so why radiation and nivo, which combo jas the better outcome?

Unfortunately, we are unable to answer specific medical questions on our blog. We recommend your mother speak with her treatment team about her options and possible treatment combinations. If you would like to make an appointment for a consultation with a Memorial Sloan Kettering physician, please call our Physician Referral Service at
800-525-2225 or go to http://www.mskcc.org/cancer­care/appointment. Thanks for your comment.

My husband was diagnosed with squamous cell carcinoma of the left lung in June of 2014. He is 70 and has smoked off and on since he was 18 years of age. However, before his diagnosis he had not smoked cigarettes for over 6 years, although, he was still smoking marijuana on occasion for debilitating back pain. He started treatment in late October with 5 days of radiation for 6 weeks, resulting in the tumor being practically absent before he started his chemotherapy in March of 2015. His chemotherapy was delayed due to changes in insurance, and at that time it appeared his tumor was returning, however; there was no metastases to any lymph nodes or other sites per PET scan. After a round of Gemzar and Carboplatin the tumor was shrinking but very little. Then after a round of Taxotere and another PET scan there was evidence of growth of the tumor. My husband will be starting Immunotherapy next week because his physician said that it tends to work better on lung cancer that is caused from smoking. Is this true and what is the success rate, as well as, any side effects? Thank you.

Thank you for replying to my previous question. The update regarding my husband is that he has started the Opdivo treatment and will be having 280mg (?) every two weeks. Although it is too soon to notice anything regarding the left lung cancer, after 4 days he is feeling better and is not as tired as he was with chemo following his first treatment. So far no side effects have been noticed either. He will have 3 more treatments and then another PET scan will be performed to see if the results are good or if there is any change in the tumor. My husband is also the first patient that is receiving the Immunotherapy from his physician, so he is just as excited as we are to see the results.. I would like to know did your patients in the research show any improvements after 6-8 weeks?

Gail, we consulted with Dr. Jedd Wolchok on your question, who responds “Some responses to immunotherapy have occurred in a short time like this.”

My mom is ext scl and I have seen trials showing significant results w keytruda. Is this a compassion drug where we could request to try? And how soon would a sclc approval take now that they've seen success? Maybe it will be on label soon? Of course I would love to get her in a trial but looks like you have to travel to locations? And most require very healthy patients- well 2nd line ext scl may not be ideal after chemo right?

Sonja, thank you for your question. We suggest your mother consult with her physician about her best treatment options, including possible clinical trials. Keytruda is approved for certain patients with non-small cell lung cancer, but not small cell lung cancer.

If you are interested in learning more about clinical trials testing Keytruda, you also might check the government web site listing here:


If you’d like to make an appointment for a consultation 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.

What specific test should be done before a patient starts immunotherapy for lung cancer?

Kathryn, according to Dr. Wolchok there is no specific test yet that a patient should have based on the research described in this blog post. He hopes there will be such predictive tests in the future.

There is a test that looks for PD-L1 expression, to determine which patients are likely to respond to the antibody drug pembrolizumab, but that is a different kind of immunotherapy than what is described here.

Thank you for your comment.

I am a 69-year-old, otherwise healthy, woman with stage four NSCLC, diagnosed three years ago. I have been through chemotherapy and stereotactic radiology. I have had no treatment for the last year because my cancer has remained stable. I am a former smoker and I am very interested in the immunotherapy. Are there any trials going on in the Boston area? Also what was the proposed results of undergoing this therapy? I have read various accounts such as prolonging one's life by X number of months and have also read that it could eradicate the cancer.

Dear Robin, we are sorry to hear about your diagnosis. Evaluating immune therapies for people with lung cancer is an active area of research at Memorial Sloan Kettering and at other institutions around the country. To browse through open clinical trials in your area, please visit www.clinicaltrials.gov. Our search for key words “immune” and “lung” yielded the following results for open trials in Massachusetts: https://www.clinicaltrials.gov/ct2/results?term=immune+and+lung&recr=Op…
We hope this is helpful.

Do you know of any people being treated with pembrolizumub or any other immunotherapy medications for stage IV metastatic melonoma after having had a kidney transplant and currently off any immunosuppresent medications. I have found 1 paper on ipilimumab but it was only on 2 people. Regards

Jo, thank you for reaching out. We consulted with one of our MSK experts about your question who responds: “It’s a great question and only anecdotal data. Best for an in-person discussion.” If you’d like to arrange for a consultation with MSK’s experts to discuss treatment options, please call 800-525-2225 to make an appointment or go to https://www.mskcc.org/experience/become-patient/appointment for more information. Thank you for your comment.

My husband (62) has Stage IV NSCLC - KRAS
He had right lung removed 7/14, (radiation & chemo before surgery) small tumor on left lung removed 2/15, 3 cm brain tumor removed 3/15 followed by whole head radiation. Just completed 2 cycles of Opdivo and tumors have spread and grown. Now going for SRS to 3 tumors in the brain. Next treatment will be taxotere as he does not qualify for clinical trial because of brain mets.He has tolerated all of his treatments like a pro. Do you have any trials that he'd qualify for?

Thanks for your time.

Hi AM, we have a number of clinical trials for NSCLC. It would be best for you to speak with one of our referral specialists about which trials might be right for your husband. You can call 800-525-2225 to learn more. Thank you for your comment.

During clinical trials of Opdivo what percentage of patients with NSCLC improved and what percentage noticed an increase in the growth/spread or more aggressive growth of their tumors? Also was the increase in growth of tumors noticed within the first or second month of treatment?

Gail, thank you for your question. We consulted with MSK medical oncologist Matthew Hellmann, who provides this response:

The response rates to Optivo in patients with NSCLC have ranged between 15-25%, and many responses can occur early (after 1-2 months), while some other responses occur later in the course.

Here are links to two studies regarding treatment of NSCLC with Optivo (nivolumab):



Optivo can be an important and transformative therapy for some patients with NSCLC, but unfortunately not all. We are working hard on translational and clinical research to better be able to identify who will best respond to Optivo and find new combinations of therapies to help more patients with NSCLC.

Thank you for your prompt response. Unfortunately my husband has passed. He had 3 treatments of Opdivo over approximately 3 months. At first he seemed to respond positively pretty quick because he did feel a little better and was able to eat more after several rounds of the Chemotherapy and radiation. However, after the second treatment of Opdivo his tumor started growing faster and he started having negative effects. As you mentioned above, Opdivo might not be the answer for everyone. His cancer became so aggressive over the next couple of months after his first two treatments with Opdivo that the one tumor became 3X larger and another one started to grow near his esophagus. He passed away two months after his third treatment of Opdivo, with two more hospitalizations in that time. I had hoped that this would allow him to live a little better a little longer. Although I am responding to this blog with the truth about what happened to my husband, it is in no way to discourage any other person interested in electing to try Opdivo with hopes that it can help a loved one. God Bless

Gail, we are so sorry for your loss. We send you our deepest condolences.

Thank you for getting back to me. Unfortunately we live in the UK and do not have any access to your hospitals there.
The oncologist here has decided to air on the side of caution and go with Ipilimumab as there have been a couple of successful attempts at treating someone with a histoey of a Renal Transplant and hopefully my Dad will have the same success. If you have any information about immunotherapy and transplant patients that you can share with me or point me in tje right direction I would very much appreciate it.

It seems like this new class of anti cancer drugs has a very promising future. Immunotherapy is still in its infancy in development and application so treatment is going to be trial and error until the most effective combinations are determined afterwards. In addition, new immunotherapy drugs will hopefully continue to be developed thru dedicated research from scientists worldwide. Imagine what another decade will yield with Big Pharma now on board?

Im in the uk and my mum has been diagnosed with lung cancer (adencarcianoma) she does not smoke but did care for her father for years who did smoke around her ( passive) which has spread to her liver ,she feels fine apart from a cough and in good health, shes been told she doesn't have the "squamous" no-small cell so cant have immunotherapy ? is this true or are there other immunotherapys that have been working in the US for people in my mums position.

Sean, we sent your questions to Matthew Hellman, who is one of our experts in immunotherapy for lung cancer, and he responded, “Anti-PD-1 immunotherapies are approved in the United States for patients with both squamous and non-squamous non-small cell lung cancers. They are approved only in patients who have previously received chemotherapy. It may well be that anti-PD-1 therapies are approved only for squamous cell lung cancers in the UK. I would suggest talking to your mother’s doctor about what the best therapies and/or clinical trials would be.” Thank you for your comment.

I find myself identifying with Gail, whose husband passed away recently following treatment with Opdivo. My fiance has head and neck cancer, and following 3 "clinical" treatments with Opdivo, no further tumors have developed... but the tumors he had prior to beginning treatment with Opdivo have now tripled in size. Should this be considered a failure, and Opdivo stopped?

Dear Susan, we are sorry to hear about your fiancé’s diagnosis. We are not able to offer a specific medical opinion or recommendation about his treatment on our blog. It’s best that he follow up with his oncologist to discuss what would be the appropriate next steps in his treatment plan. Thank you for reaching out to us.

My sister has been diagnosed with small cell lung cancer. She has undergone 3 rounds of chemo at this time and has 3 more to go as well as having her brain undergo radiation at the end. Does Immunotherapy work on small cell lung cancer or only non small cell lung cancer?

Dear Staphanie, we are sorry to hear about your sister’s diagnosis. Clinical trials at MSK are testing immunotherapy drugs in all settings: before and after surgery for early stage lung cancers, as first-line therapy in patients with advanced lung cancers, and in patients who have previously received chemotherapy. There are trials available for multiple forms of lung cancer, including non-small cell lung cancer and small cell lung cancer.

Browse through our open trials investigating immunotherapy and other novel treatments for people with lung cancer here: https://www.mskcc.org/cancer-care/types/lung/clinical-trials. If your sister has any questions about these trials or would like to make an appointment, please ask her to call our Physician Referral Service at 800-525-2225. Thank you for reaching out to us.

Hello. My sister, age 66, has just been diagnosed with stage IIIA adenocarcinoma of the lung. During the past 45 years, she has smoked a pack/day of cigarettes. She has met with an oncologist and he is suggesting treatment with what he calls traditional chemotherapy and radiation. We asked about the possibility of molecular/genetic profiling and immunotherapy and/or targeted therapy. He told us that this is only done with stage IV lung cancers. With the research being done at your facility, is the information he provided current, or are you using immunotherapy for my sister's type of cancer? If you could get back to me asap, I would appreciate it, as therapy is to begin in a few weeks. Thank you so much for any information you can offer.

Dear Becky,
We forwarded your question to MSK lung cancer oncologist Matthew Hellmann and this was his response:

“Surgery and/or radiation and/or chemotherapy are the mainstays of treatment for patients with stage I-III lung cancers. The goal of that treatment is cure and the combination of surgery/radiation/chemotherapy can make that possible. Research is ongoing to investigate how to integrate immunotherapies in the treatment of patients with stage I-III lung cancers, but this is still in early stages and there is not yet evidence to say this should be a standard approach.”

We hope this is helpful to you and your sister.

My husband was diagnosed with Stave IV NSCLA in Sept 2011. After two types of chemo, and 2 sets of radiation his cancer returned in December of 2014. In June of 2015 he started on the immunotherapy. He has been cancer free ever since. Almost 5 years, practically a miracle!

Dear Ruth, we are glad to know that your husband is cancer free and wish him our best. Thank you for sharing your thoughts on our blog.

My husband diagnosed Lung Cancer (non-small cells - Squamous cell carcinoma) stage 3B since May 25, 2016. He didn't start any treatment yet. It is possible do the targeted therapy or immunotherapy before do the chemotherapy or Radiation? Or has to do the chemotherapy and radiation first?