The Next Generation of Agents for Lung Cancer

Tony Mok, MD

16th International Lung Cancer Congress

At the 16th Annual International Lung Cancer Congress, Tony Mok, MD, Professor of Clinical Oncology, The Chinese University of Hong Kong, provided an overview of the next generation of agents, taking stock of the recent past for insights into the future of drug discovery.

Drug discovery is rarely, if ever, an overnight occurrence. Rather, as Mok described it, the journey from data to practice is often decades in the making.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first generation of agents to show success in the management of lung cancer. These drugs, which block the signal from EGFR that tells cells to grow, can be used without chemotherapy as a first-line treatment for advanced non–small cell lung cancers (NSCLCs) that have certain mutations in the EGFR gene. However, it was not until the recent discovery of EGFR mutations that these agents could yield response rates over 70%.

“Only with the discovery of the biomarker do we have the ability to know which is the right target and achieve such high response rates,” Mok explained. “Prior to the biomarker, we had a response rate of 10% to 20%. After it was discovered, we moved into the first-line situation alongside standard chemotherapy.”

From there, combination regimens have been developed to enrich and improve therapy, and these agents have since been extended to the adjuvant and stage III settings. If results from the ongoing ARCHER 1050 phase 3 study turn out to be positive, dacomitinib will become the fourth EGFR-TKI available for the first-line setting.

“Eventually, we learn how to overcome resistance,” said Mok. “This is the life cycle we have gone through for the EGFR mutation, but can we duplicate this for the future?”

Highlighted by Mok, the influx of new and effective agents on the market poses several important questions: “What is the best sequence to use with these agents, and what is the best dosage? When we have a third generation that works, should we put it first? How do we combine TKIs with immunotherapy? And finally, when we use these agents, should we do so concurrently or sequentially?”

Providing answers to all these questions, Mok said, represents the next phase of drug development.

Next Generation of ALK Inhibitors

As Mok detailed, the list of ALK inhibitors is not very long. Crizotinib is the current standard, but the ALEX study, a randomized phase 3 trial comparing alectinib with crizotinib in treatment-naive patients with ALK-positive advanced NSCLC, may soon change this paradigm. “The study is accruing quite well,” said Mok. “Hopefully, within a year and a half we may be able to get some answers.”

Another study from the National Cancer Institute is comparing a number of different TKIs to determine the optimal sequence of ALK inhibitors and raises additional questions for clinicians: “Is progression-free survival the best end point or is it overall survival?” Mok asked the audience. “How do we develop rational combinations given the large number of bypass tracks that can mediate ALK TKI resistance? Given that 30% to 40% of ALK-positive patients may have brain metastases, how do we determine the most effective ALK inhibitors for penetration of the central nervous system?”

Targeting ROS1 and NTRK1

Although there are several ongoing studies testing numerous potential agents, Mok put emphasis on entrectinib because “this is one agent that potentially can be good for both ROS1 and NTRK.”

A basket study, a new form of clinical trial design that explores responses to drugs based on the specific mutations in patients’ tumors rather than where their cancer originated, is also under way. The STARTRK-2 study will test entrectinib in patients with NSCLC, colorectal cancer, and other solid tumors. As long as patients are ROS1 positive, said Mok, they can be put on the drug.

“We are transitioning from tissue-based to molecule-based therapy,” said Mok.

Finally, another gene that shows promise but has not been investigated is TUSC2. Data have been interesting thus far, he said.

Epigenetics and Future Discovery

Despite these exciting developments, Mok concluded his talk with a reminder of an area in which lung cancer therapy may lag behind the rest of oncology.

“Epigenetics has been around for over a decade,” he said “and a number of therapies have been approved for hematologic disorders, so it is possible that epigenetics can make a difference in cancer management.” For lung cancer, however, the response rate is either 0% or 2%.

“More research needs to be done in this field,” Mok concluded. “We need to look at this area from a different angle. We have to invest in discovery of pathways that will offer a new direction for investigation….To move the field further, we still have to think outside the box.”

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