ASCO: Chemotherapy Key Part of Curative Lung Cancer Therapies

Mark G. Kris, MD

As part of our coverage of the 2014 ASCO Annual Meeting, Cancer Network is speaking today with Mark G. Kris, MD, the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center. On Tuesday, June 3, Dr. Kris will serve as the chair for an Education Session titled “Why Is Chemotherapy Here to Stay in Lung Cancer?”

-Interviewed by Leah Lawrence

Cancer Network: Thank you for speaking with us today, Dr. Kris. First, can you tell us why this is an important topic for an education session? Is there a debate of the use of chemotherapy in treating lung cancer?

Dr. Kris: I wouldn’t quite say that there is a debate, but there is an impression that the therapy of lung cancers has switched to targeted therapies or immune therapies. Looking at the ASCO abstracts this year that would be an easy conclusion to draw. But there is an indisputable fact that no matter what target you can identify in a patient’s tumor, be it PD-L1 or a BRAF mutation, at some point in a patient’s illness they will be receiving chemotherapy. As we look at entire care of people with lung cancer it is very important to remember that virtually every single one will receive chemotherapy, and that we need to pay attention to choosing the best chemotherapy. We also need to think about doing research in chemotherapy. Clearly, we can do a better job, and we need more research to find the best drugs. Also, we need to find a way to use them with our targeted therapies.

Cancer Network: What were some of the more successful chemotherapeutic agents incorporated into lung cancer treatment during the last few decades?

Dr. Kris: The theme of ASCO this year is 50 years of progress in science and society. It is important to reflect back on the accomplishments of the oncology community worldwide and particularly in fighting an illness like lung cancer. I think the single most important contribution of chemotherapy is that it has enhanced the cure rate. When you couple chemotherapy with surgery, either before or after surgery, or you couple chemotherapy with radiation in patients with localized or locoregional spread of their lung cancer, both small-cell and other cell types, you can cure patients. You can enhance the cure rate over radiation alone and surgery alone.

As it stands today in lung cancers, the only modality that has been shown conclusively to improve cure rates is chemotherapy. That fact needs to be stated and also docs treating people with lung cancer need to look for every opportunity to make sure that patients who could benefit from this potentially curative approach are identified, and then once identified that the best drugs are given, and that patients receive the optimum supportive care to ensure that drugs that can enhance the cure rate are delivered to them.

Cancer Network: How has the role of chemotherapy evolved in the neoadjuvant setting?

Dr. Kris: Neoadjuvant chemotherapy is a very effective approach. Randomized trials that have been done show that it is every bit as effective as giving chemotherapy afterwards. It has several advantages over receiving postoperative or adjuvant chemotherapy. The first one is that you can assess whether or not an individual patient is benefiting from that chemotherapy and, if it is not leading to benefit, it can be stopped. In the adjuvant setting, giving the admittedly tough drugs like cisplatin to our patients is very difficult to give cycle after cycle not knowing if the drug is helping. It is tough for the patient, first and foremost. It is tough for the health care people too, because the drugs have toxicities and a lot of effort goes into managing those toxicities, and you just don’t know if it works. Whereas, in the neoadjuvant setting, you know if that drug is working. If it is, you continue it, and you can see the benefit.

The second reason that it is important to use the neoadjuvant approach is that we have more drugs available. Back when we only had one drug, we really did not have another option. If we give, for example, a cisplatin-containing chemotherapy regimen and find that it is not helpful we can switch to a non-cisplatin-containing regimen. That is something that has only happened in last few years.

The last opportunity that comes with giving drugs in the neoadjuvant setting is that we can use the pathologic evaluation of the tumor at time of surgery to measure the effectiveness of chemotherapy regimen, the so called pathologic response or pathologic complete response. It has been shown in lung cancers that the pathologic complete response is ultimately a surrogate for long-term outcomes for the patient for survival. Right after surgery you can tell how good a chemotherapy regimen is by its ability to lead to these pathologic complete responses. For an adjuvant trial it takes almost a decade to get a read out; whereas, here in the neoadjuvant setting you can get it much quicker.

We have also seen the tremendous benefits in using this neoadjuvant approach and the careful examination of the tumor specimens at the time of surgery with the development of new drugs. Ado-trastuzumab emtansine in breast cancer was just approved specifically in the neoadjuvant setting. It is a way to help accelerate new drug development. Giving patients additional options, stopping ineffective therapies, switching to better therapies, assessing long-term outcomes via pathologic response, and testing new drugs in the neoadjuvant setting… they are all of the advantages of neoadjuvant therapy. I think that is something that is going to accelerate research and improve care. It is important that it be pushed forward, and chemotherapy is integral to that whole approach.

Cancer Network: How has chemotherapy been adapted to be used in conjunction with other treatments such as radiation, targeted agents, or immunotherapies?

Dr. Kris: First talking about the use of chemotherapy with radiation, there is a huge amount of research over the last 30 years now that when first you compared radiation alone to chemotherapy with the radiation there clearly was benefit from giving the two modalities together. The greatest degree of benefit was found when the chemotherapy was given simultaneously with the radiation. That was found in small-cell and in adenocarcinoma. It is now a standard of care in patients with locoregional spread that are not surgical candidates to give simultaneous chemotherapy and radiation.

With targeted therapy, and I will focus mainly on patients with EGFR mutant cancers first, it is clear that chemotherapy is very effective in these patients. The response rates to chemotherapy in the IPASS trial, the famous trial that compared gefitinib to chemotherapy initially, in those patients with EGFR mutant lung cancers, their response rate to chemotherapy was double that of patients that did not have EGFR mutant cancers. Chemotherapy works, and it works even better in people with EGFR mutant cancers. There is a huge possibility to use those drugs together. I think what we are going to see in the coming years is research to try to sequence chemotherapy and targeted therapies. Interesting too, in the ALK rearranged lung cancers, the effectiveness of pemetrexed is more than double that of earlier trials where people were unselected. It is quite clear that chemotherapy is effective in these patients. It is an important observation, number one for those patients, that chemotherapy does and can work, and also perhaps they can teach us about what makes chemotherapy effective. We still don’t have good predictive markers for any chemotherapy, and it may be something about these ALK rearranged or EGFR mutant cancers that can teach us about that.

The last thing is as immunotherapies have become available, we are only now trying to figure out what is the best way to give chemotherapy and immune therapies, either targeting CTLA-4 or targeting PD-1 or PD-L1. One thing we know already is that the killing that can happen with chemotherapy can release antigens that would make cancer cells more susceptible to treatment with PD-L1 or anti-CTLA-4 therapies. Folks are employing those strategies now, and I think you are going to see research over the next 5 years that looks for the sequencing of chemotherapy and radiation with immune therapies. The common denominator to all of these approaches is using chemotherapy, drugs targeting aspects of the cell cycle, IV chemotherapies, or traditional chemotherapies, they all have role with targeted therapy, with radiation, and with our newer immune approaches.

Cancer Network: Finally, looking to the future, why do you think that chemotherapy in lung cancer is here to stay?

Dr. Kris: Chemotherapy is here to stay first and for most because it can cure patients. Today it is the only modality that has been proven to improve curability with radiation or with surgery. None of the targeted therapies, none of the immune therapies have been proven to do that yet. The second thing is clearly chemotherapy will be additive, adjunctive, and synergistic with our targeted therapies and with our immune treatments as well. Lastly for patients that don’t have a target, chemotherapy can help them. It can lengthen life. It can control symptoms and has the potential to bring benefit to almost any patient with lung cancer. It does not do that often enough, but it is an option for patients. For the whole spectrum of people with lung cancers chemotherapy helps in and of itself, it adds to our other effective therapies, and I think we are going to see research over the next many decades on how to best use chemotherapy with our many new approaches. The bottom line is going to be more effective cancer treatments and hopefully more curative cancer treatments.