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PER® New York Lung Cancer Symposium

Crizotinib, a c-MET/ALK/ROS1 tyrosine kinase inhibitor, received accelerated approval from the FDA in 2011 for ALK-positive non-small cell lung cancer (NSCLC) based on two single-arm post-chemotherapy trials. While a phase III trial testing crizotinib versus chemotherapy in the frontline setting is ongoing, “The NCCN recommendation is to use crizotinib as a standard agent even prior to chemotherapy in ALK-positive advanced NSCLC patients,” Alice T. Shaw, MD, PhD, said in a presentation at the 8th Annual New York Lung Cancer Symposium in New York City.

Now, next-generation ALK inhibitors are being developed to address the unmet need of those patients who are becoming resistant to crizotinib. Researchers are also accumulating data on the spectrum of resistance mutations that occur in patients who are treated with the drug.

Shaw, an attending physician at the Massachusetts General Hospital Center for Thoracic Cancers, assistant professor of Medicine at the affiliated Harvard Medical School, and clinical investigator at MIT’s David H. Koch Institute for Integrative Cancer Research, discussed resistance mechanisms and next-generation ALK inhibitors in clinical trials that are poised to be broadly available in the next few years.

Approximately 3% to 5% of NSCLC patients harbor a rearrangement in the ALK gene. Rearrangements in ROS1, a receptor tyrosine kinase structurally related to ALK, have also been identified.

“The data so far show that critotinib is effective for ROS1-positive patients,” Shaw said. “The drug is not yet approved for ROS1-rearranged NSCLC, but both ALK and ROS1 are important molecular targets that oncologists need to be aware of in NSCLC.”

Patients with these two types of oncogene-addicted lung cancer tend to be about 10 years younger than other lung cancer patients, are typically light or never smokers, and are commonly diagnosed with adenocarcinoma of the lung, said Shaw.

Among the 36 ROS1-positive patients treated with crizotinib in early-stage research, all have had some degree of response. The median progression free survival has not yet been reached. While less than 10% of ALK-positive patients have intrinsic resistance to crizotinib, so far, a similar intrinsic resistance has not been documented among ROS1-positive patients.

Dr. Shaw on Monitoring Crizotinib-Related Side Effects

While crizotinib works very well, “at some point patients do develop resistance, typically around 9 to 12 months” after starting treatment, said Shaw.

A spectrum of secondary mutations have been identified in the ALK kinase itself. The most common is the 

 “gatekeeper” mutation. Amplification of the ALK fusion gene has also been identified. In about two-thirds of resistant cases, no resistance mutations in ALK are identifiable, and activation of other signaling pathways, such as the EGFR pathway, may mediate resistance to crizotinib.

Understanding these mechanisms has helped to accelerate the next wave of ALK inhibitors, said Shaw. The next generation ALK inhibitors entering the clinic have primarily been studied in ALK-positive NSCLC patients who have acquired resistance to crizotinib. Many of these drugs also target ROS1 rearrangements, Shaw noted.

 gene mutations have so far shown different degrees of response to the novel ALK inhibitors. The most advanced of these are LDK378 (Novartis) and alectinib (Roche).

Based on positive phase II data, LDK378 is now being tested in two phase III trials in both treatment-naïve patients and those previously treated with both chemotherapy and crizotinib. The drug has shown activity against both ALK and ROS1.

Alectinib selectively targets ALK—but not ROS1&mdash;and has shown a high response rate in crizotinib-naïve Japanese patients.

Both of these agents have been shown to be active on brain metastases.

Going forward, the next questions for researchers are whether using these new ALK inhibitors upfront could prolong the time to resistance and how to overcome resistance that develops even to these new drugs.

View coverage from the New York Lung Cancer Symposium

Next-generation ALK inhibitors are being developed to address the unmet need of patients with non-small cell lung cancer who are becoming resistant to crizotinib.

Next Generation ALK Inhibitors Poised to Become  Standard of Care for Crizotinib-Resistant Patients

While targeted and immunotherapy drugs have recently shown promise in non-small cell lung cancer (NSCLC), similar developments in small cell lung cancer (SCLC) have not materialized.

“Standard combination chemotherapy for advanced, extensive-stage SCLC has not changed substantially in the last 30 years,” said Charles M. Rudin, MD, PhD, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center in New York. Rudin provided an overview of the biology of the malignancy as well as ongoing research to identify and test new drugs targeted at SCLC during the 8th Annual New York Lung Cancer Symposium in New York City on November 9.

“There is a critical need for effective therapy in advanced forms of this disease,” said Rudin.  Although Rudin said there have been recent advances in the use of radiotherapy to treat limited-stage SCLC, he noted that two-thirds of patients with SCLC present with extensive-stage disease at diagnosis.

A particularly aggressive type of lung cancer, SCLC is related to smoking or exposure to secondhand smoke, comprises approximately 15% of all lung cancer cases, and is characterized by rapid progression and a median survival of less than 12 months. Patients initially respond to chemotherapy but almost all those with extensive disease subsequently relapse.

To understand the molecular biology of SCLC and create a roadmap of the key driver mutations in these tumors, researchers have sequenced the SCLC genome and found a high density of mutations likely due to the carcinogenic effect of tobacco smoke. “Finding driver mutations is a real challenge,” said Rudin.

Part of the challenge in identifying potential targeted therapies is the prevalence of inactivating mutations in tumor suppressor genes such as 

, and only infrequent gain-of-function mutations in oncogenes such as 

 family members. “The bottom line is that many of the mutations we find are tumor suppressors, rather than oncogenes,” said Rudin. “These tumor suppressors are not each targets for therapy.”

Researchers are now focusing on finding those mutations that are relevant to tumor growth and progression and distilling out passenger mutations. An important goal is to identify anticancer drugs that kill tumor cells that are resistant to chemotherapy, since additional agents that kill the same chemotherapy-sensitive cells are not likely to lead to a survival improvement, according to Rudin.

One approach has been to identify gene families and pathways. The 

gene has been found to be unregulated in some of these tumors. In vitro data show that inhibiting SOX2 can almost completely inhibit the growth of SCLC cell lines overexpressing SOX2. As a transcription factor, this protein may be difficult to target with drugs, Rudin noted, but genes downstream of SOX2 may be feasible targets to inhibit signaling of this pathway.

Current studies are focusing on the Hedgehog pathway, epigenetic regulatory pathways, and DNA damage repair mediated by PARP1. While preclinical studies have shown promising activity of Hedgehog inhibitors, this activity has not translated to improved outcome when vismodegib was combined with the chemotherapy agents cisplatin and etoposide in patients with advanced SCLC.

An ongoing study targeting the DNA damage pathway is a combination phase I/II trial of chemotherapy with the PARP inhibitor veliparib that includes patients with extensive-stage SCLC.

 Investigators are seeking to randomize 168 patients with SCLC or several other types of lung cancer to cisplatin and etoposide with or without veliparib as frontline therapy.

Researchers also are exploring whether combining veliparib with temozolomide provides greater benefit than temozolomide alone in patients with relapsed or refractory SCLC.

A previous study showed that temozolomide is active in patients who have progressed after one or two chemotherapy regimens, including patients with brain metastases.

Agents that inhibit proteins from the bromodomains and extra terminal (BET) domain family are also being studied in SCLC. BET proteins regulate epigenetic alterations and chromatin remodeling. The BET inhibitor GSK525762 currently is being tested in a phase I trial in patients with various tumor types, including patients with SCLC.

			Cisplatin and etoposide with or without veliparib in treating patients with extensive stage small cell lung cancer or metastatic large cell neuroendocrine non-small cell lung cancer. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01642251. Updated November 4, 2013.

			Temozolomide with or without veliparib in treating patients with relapsed or refractory small cell lung cancer. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01638546. Updated September 18, 2013.

			Pietanza C, Kadota K, Huberman K, et al. Phase II trial of temozolomide in patients with relapsed sensitive or refractory small cell lung cancer, with assessment of methylguanine-DNA methyltransferase as a potential biomarker [published online ahead of print January 6, 2012]. 

			A study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of GSK525762 in subjects with nut midline carcinoma (NMC) and other cancers. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01587703. Updated September 12, 2013.

Targeted Therapies Explored in Small Cell Lung Cancer

Naiyer A. Rizvi, MD, an associate attending physician, Memorial Sloan-Kettering Cancer Center, discusses PD-1 and PD-L1 antibodies in development for the treatment of lung cancer.

Rizvi says the anti-PD-1 antibodies nivolumab and MK-3475, and the anti-PD-L1 antibody MPDL3280A, are all being developed as treatments for stage IV lung cancer. Early studies of these agents have shown a response rate in the 20% range in patients with heavily pre-treated lung cancer who are resistant to chemotherapy and have failed all standard therapies. Rizvi says a 20% response rate is very encouraging for this group of patients.

Many of these patients have also showed durable responses, Rizvi says. Recently, the data from the nivolumab trial were updated to show a 2-year survival of 24%, which Rizvi says is a very high number for that patient population.

Dr. Rizvi on PD-1 and PD-L1 Inhibitors in Lung Cancer

Alice T. Shaw, MD, PhD, an attending physician in the Center for Thoracic Cancers at Massachusetts General Hospital, discusses monitoring adverse events associated with crizotinib when treating patients with ALK-positive lung cancer.

Shaw says that a newly diagnosed patient with ALK-positive lung cancer should take an ALK inhibitor as their first therapy. Crizotinib, an ALK inhibitor, is an easy pill for patients to tolerate and is taken twice a day with food to minimize nausea.

Shaw says she always warns her patients about the onset of visual symptoms, as almost all patients will experience some visual disturbance. These symptoms are mild and are usually triggered by going from a dark environment to a light environment.

Patients’ liver function should also be monitored, Shaw says, as crizotinib carries the risk of transaminitis. Shaw suggests monitoring liver function in patients that are taking crizotinib every two weeks.

Patients on crizotinib can do well for long periods of times- anywhere from 8-10 months to 2-4 years. For patients that remain on crizotinib for long periods of time, Shaw recommends doing surveillance brain MRIs. Even if patients have no history of brain metastases, a proactive approach is recommended, since the risk of developing brain metastases is high, Shaw says.

Alice T. Shaw, MD, PhD, an attending physician in the Center for Thoracic Cancers at Massachusetts General Hospital, discusses monitoring adverse events associated with crizotinib when treating patients with ALK-positive lung cancer

Leaders in thoracic medical oncology from major cancer centers will come together Saturday to discuss advances in the field of lung cancer treatment during the 8th Annual New York Lung Cancer Symposium in New York City. The one-day meeting is hosted by Physicians’ Education Resource, LLC (PER).

Mark G. Kris, MD, one of the symposium’s program directors, said the conference will cover next-generation approaches and drugs for treating patients with advanced non-small cell lung cancer (NSCLC), including acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and new treatment options for patients with tumors that test positive for the 

gene translocation. Revised strategies for treating small cell lung cancers, an update on squamous cell lung cancers, and the potential of immune therapy approaches also will be discussed.

“It’s a great opportunity to meet the local and international experts to learn about controversies today and to see what treatments are going to be available in your pharmacy within the next year or so,” said Kris, who is the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan-Kettering Cancer Center in New York City.

Román Pérez-Soler, MD, who also is a program director, said the meeting helps fill a need for oncology specialists to keep abreast of rapid advancements in the field.  Pérez-Soler is chairman and chief of the Department of Medical Oncology at Montefiore Medical Center and an associate director of Clinical Research at Albert Einstein Cancer Center in Bronx, New York.

“The amount of data being generated on a monthly basis is quite amazing,” said Pérez-Soler. “There is a need to update people almost constantly. It’s a very useful program for people who want to catch up on what’s going on in lung cancer treatment.”

The symposium will feature these presentations:

		Molecular Targeted Agents for Stage III NSCLC

		New Horizons for Small Cell Lung Cancers

		New Treatments for Squamous Cell Lung Cancer

		PD-1/PD-L1 Inhibition: What Does the Future Hold?

In addition, there will be debates on whether bevacizumab-based therapy should be the front-line standard of care for stage IV nonsquamous NSCLC, and whether there is an optimal tyrosine kinase inhibitor in 

-mutant cancers. There also will be a discussion of challenging cases that confront clinicians.

Faculty members scheduled to make presentations include Alice T. Shaw, MD, of Massachusetts General Hospital and Harvard Medical School; Bryan J. Schneider, MD, of New York Presbyterian-Weill Cornell Medical Center; and Charles M. Rudin, MD, PhD, and Gregory J. Riely, MD, PhD, of Memorial Sloan-Kettering Cancer Center.

Leaders in thoracic medical oncology from major cancer centers will come together Saturday to discuss advances in the field of lung cancer treatment during the 8th Annual New York Lung Cancer Symposium® in New York City.

PER® New York Lung Cancer Symposium | Conference

Next Generation ALK Inhibitors Poised to Become Standard of Care for Crizotinib-Resistant Patients

Targeted Therapies Explored in Small Cell Lung Cancer

Dr. Rizvi on PD-1 and PD-L1 Inhibitors in Lung Cancer

Dr. Shaw on Monitoring Crizotinib-Related Side Effects

NY Symposium Tackles Emerging Agents, Pressing Questions in Lung Cancer