Mark G. Kris, MD, Discusses Emerging Targets and Treatments for Lung Cancer

Mark G. Kris, MD

The 7th Annual New York Lung Cancer Symposium offered a comprehensive overview of the latest research into targets and treatment strategies for patients with lung cancer.

During the one-day symposium, more than a dozen oncologists presented information on emerging therapeutic targets for squamous non—small cell lung cancer (NSCLC); the optimal application of tyrosine kinase inhibitors (TKIs) in lung cancer driven by EGFR mutations or ALK rearrangements; strategies for patients with poor performance status; approaches to maintenance therapy; and treatments in the pipeline.

In an interview with Oncology & Biotech News, Mark G. Kris, MD, chief of the Thoracic Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York City and program co-director of the New York Lung Cancer Symposium, offered insights about those and related issues.

OBTN: The discovery of therapeutic targets in the squamous form of NSCLC is a critical area, since there are fewer effective therapies for that disease subtype than for adenocarcinoma. What is on the horizon for patients with this disease?Dr Kris: Worldwide, squamous cell carcinoma (SCC) is a very common form of lung cancer, and in the United States it comprises approximately 25% of lung cancers. Since we’ve had many new developments in adenocarcinoma, the focus has been on that illness, whereas in the past it was on small cell lung cancer because of its sensitivity to chemotherapy. One thing we’re learning now is that SCC, too, has characteristics that can be exploited to get better results for patients.

The first example of that is the trial by Giorgio Scagliotti, MD, PhD, that analyzed the effects of different chemotherapies—either pemetrexed or gemcitabine in combination with cisplatin—in patients with advanced NSCLC (J Clin Oncol. 2008;26[21]:3543- 3451). The pemetrexed combination was more successful in lengthening life in adenocarcinoma, while the gemcitabine combination was better in patients with SCC.

Another example is the paradox of bevacizumab. In bevacizumab’s early clinical testing, while patients with SCCs had severe and immediate shrinkage of their cancers, it led to hemoptysis and often fatal consequences. There was a tremendous sensitivity to bevacizumab that precluded safe use, which is another reason it’s very important that we determine whether a patient has SCC.

We now know that, just like in adenocarcinoma, there are specific drivers for SCC. We’ve found amplification of the FGFR1 gene and mutations in PI3 kinase, PTEN, and DDR2, and we’re now developing clinical trials to find agents that go after and potently inhibit those targets. It’s an emerging area just ripe for benefit and, as the years go on, I think we’re going to see the same kind of benefit for patients with SCC as we have with adenocarcinoma.

There has been recent success with the use of TKIs to treat patients whose lung cancer is driven by EGFR mutations or the ALK rearrangement. What’s new in this area?

Any oncologist treating lung cancer has seen the very dramatic benefit that can occur with the use of TKIs like erlotinib or gefitinib in patients whose tumors have EGFR mutations. With a proper dose, you can pretty much guarantee a response to therapy, manageable side effects, and a level of lifestyle preservation we’ve never had before. Most people continue their jobs and their participation in family life and community and athletic activities.

To find the right patients for these treatments, you need to know that they have the driver, which means you have to do mutation testing. Our guidelines have been changed to recommend testing specifically for EGFR and the ALK rearrangement at the time of diagnosis for every patient with adenocarcinoma and selected patients with SCC—those whose diagnosis is less certain because their biopsy specimen was tiny, and never-smokers, whose cancers often have an adenocarcinoma component.

While we can guarantee that the benefit from treatments like erlotinib or crizotinib will last 1 to 2 years, the agents then stop being helpful and cancer starts growing again. We’ve learned that there are three possible scenarios when that happens. First, and blessedly commonly, the cancer grows extremely slowly, by a few millimeters from x-ray to x-ray, and the patients are not harmed. In those cases, I would continue the TKI. The second possibility is that growth occurs in only one spot, and in that situation a good strategy is to obliterate the growth and then go back to the TKI, which can keep the patient alive for years. The third scenario is that the cancer is causing symptoms and growing in multiple spots, and in that case I recommend continuing the TKI and adding in another drug, generally a chemotherapy.

What should community oncologists know about treating patients with advanced NSCLC who have poor performance status or other complicating issues?

We are often faced with individuals who have been diagnosed with lung cancer, but who have problems that make therapy very difficult. Sometimes people are very sick from a malignancy, and in those cases, by treating the malignancy effectively, we can sometimes improve poor functional status. Patients who recover from that initial insult could have the possibility of receiving some other therapy later on.

When people are ill for other reasons, such as heart disease or severe rheumatoid arthritis, they are generally tough to treat. To start, make sure you know the patient’s performance status. If the patient’s Karnofsky score is less than 60—ECOG 3 or 4—no treatment is recommended other than to treat the symptoms of the cancer. We must remain steadfast in our understanding that, if patients are bedbound or wheelchair-bound, it’s very unlikely that chemotherapy or any therapy will benefit them, and we should not recommend it.

One exception is patients who have a driver mutation, since there’s clear data they will benefit from a TKI.

What are your thoughts on the value of maintenance therapy in advanced NSCLC?

We talk a lot about targeted therapies, but the single most important development that’s applicable to even more patients worldwide is maintenance therapy (MT). To me, it’s almost a nobrainer that continuing a therapy that has proven to be effective and safe in a specific patient makes all the sense in the world—it’s the ultimate targeted therapy. It gives such patients a longer time cancer-free and an improvement in survival measured in months. In fact, in the NCCN guidelines, the first recommendation for the length of therapy is that you continue until disease progression, as long as you constantly re-evaluate the patient in terms of safety, benefit, and their acceptance of the regimen.

Of course, we’re not going to continue MT if the therapy itself has become a burden to the patient, or if we don’t have good evidence of objective benefit. But for those people in whom it’s safely given, effective, and not lifestyle-impeding, all the data from virtually every trial in NSCLC says it should be continued. The PARAMOUNT trial (J Clin Oncol. 2011;29[suppl; abstr CRA7510]) that looked at MT with pemetrexed—regardless of whether you measure the time from the start of treatment or the beginning of maintenance—demonstrated months of improved survival. In POINTBREAK, although overall survival was the same, when you look specifically at patients who got MT, giving them both pemetrexed and bevacizumab, rather than bevacizumab alone, resulted in longer survival, as well.

Despite what, to me, are the very clear benefits of MT and the literature that supports it, it’s still not been fully adopted. I ask everybody to think about making MT part of their strategy.

The MARQUEE trial looked at erlotinib with or without tivantinib in patients with locally advanced or metastatic, nonsquamous NSCLC. Why was the trial terminated in October 2012?

The trial was terminated for futility, because no difference in results between the two arms could be discovered in the number of patients they randomly treated.

I have not been a proponent of the trial. The benefits of erlotinib in unselected patients are very small, and we have a growing burden, as oncologists, to focus our attention and resources on those trials with the greatest chance of benefit. In that regard, it’s very important to pay attention to phase II data. Although it’s not widely held, the phase II data on which the MARQUEE trial was based was negative; there was no improvement in outcome with the two drugs instead of the one. It made no sense to do that trial, and I’m happy to see it ended early.

What are some of the most exciting potential treatments in the pipeline for NSCLC?

We’ve had an extraordinary year for the discovery of new molecular targets and driver mutations in lung cancers. Not only have we found these targets, but in some cases there already exists a drug that will work.

For instance, we now know that rearrangements of the ROS1 gene are oncogenic, and in data presented at ASCO this year by Alice T. Shaw, MD, PhD, we were able to see that giving crizotinib to those patients pretty much guaranteed a significant response. Another group of patients are those with RET fusion genes. Barely 1 year ago, this abnormality was discovered, and already there were reports at ESMO this year that the drug cabozantinib can effectively treat these patients. From early reports, it looks like many other drugs may be effective in this setting, as well: vandetanib, sunitinib, sorafenib—drugs we already have in our pharmacies. Also discovered were abnormalities involving additional activating mutations in the HER2 gene, in the extracellular binding domain, and there’s laboratory evidence that these can be inhibited with HER2-targeted agents.

What’s happening, at the same time, is that we have multiplex screening now, platforms that are more comprehensive, quicker, cheaper, and can give you all your answers in one casting. And if these take hold, we’re going to have access to all of this mutational data.

Finally, we’re all very excited about the emergence of immune therapies, including ipilimumab, which, in addition to emerging as a treatment for malignant melanoma, is being tested in lung cancer.

This year at ASCO, we saw that a similar concept—targeting specific populations of lymphocytes—could be effective, as could the use of antibodies targeting PD-1, particularly the PD-L1 protein. While our existing therapies are beneficial, they are not curative, so we need other therapeutic strategies that are complementary to targeted therapies and to cytotoxic chemotherapy, and the emergence of anti—PD-1, anti–PD-L1, and anti-CTLA4 therapies is really a great complementary adjunct to what we can do, not just to lengthen life, but hopefully, someday, to cure lung cancer.

How should everyday oncology practice evolve in response to these growing insights about lung cancer?

We no longer give therapy for lung cancer, but for lung cancers. We’ve seen that we need to come up with the best treatment plan for each specific kind of lung cancer, and that will become more and more of a reality as we continue to find targets that are important to the growth of those cancers, particularly when we have drugs that can inhibit the effects of those targets.

In addition, we have to think with a very open mind about patients with isolated, single metastatic sites where surgery, radiofrequency ablation, or stereotactic body radiation therapy may be useful. While these treatments may not make immediate sense to us, they have, in other cancers—even in the metastatic setting—been shown to improve life. I think we’re at the stage now where we can do that in lung cancer, as well.