Molecular Targets in Non-Small Cell Lung Cancer

David R. Spigel, MD

Currently Treatable Targets

Today, the treatment options for non-small cell lung cancer (NSCLC) in the United States include targeted therapies aimed at angiogenesis (bevacizumab),EGFRmutations (erlotinib and afatinib), and ALK translocations (crizotinib). Although these agents offer patients with these genetic abnormalities options outside of standard chemotherapy, there are still many patients whose disease falls outside of these genetic parameters, and so the research continues in the effort to bring more options to more patients.“I think a huge revolution occurred in the sense that one could molecularly dissect out the pathways for non-small cell lung cancer. So when it was discovered that EGFR was not only expressed in lung cancer, but it could potentially be mutated, especially in various domains that were responsive to small molecule inhibitors, this was quite exciting,” said Ravi Salgia, MD, PhD, professor of Medicine, director of the Thoracic Oncology Program, and vice chair for Translational Research at the University of Chicago.

Dr. Piperdi on Molecular Targeted Agents for Stage III NSCLC

Piperdi is an associate professor at the Albert Einstein College of Medicine.

According to David R. Spigel, MD, leader of the phase II/III Clinical Research Program at Tennessee Oncology and program director for Lung Cancer Research at Sarah Cannon Research Institute, “Erlotinib and afatinib bind to the part of the protein that’s inside the cancer cell, called the intracellular domain, and they bind to the ATP binding pocket. When the drug sits in that pocket, it prevents that receptor from signaling other proteins and processes within the cell.” He added that the reason these drugs work so well in patients withEGFRmutations is that these cancer cells are extremely dependent on EGFR signaling. Although most of the trials of erlotinib have included broad populations unselected forEGFRmutation status, a subset of patients with tumor samples available who had EGFR-mutant tumors were shown to derive benefit from erlotinib (median overall survival [OS], 10.4 vs 3.7 months).¹Likewise, afatinib, which gained approval in the United States in July of 2013, was found in the phase III LUX-Lung 3 trial²to be associated with prolongation of progression-free survival (PFS) compared with standard doublet chemotherapy in the EGFR-mutant population (median, 11.1 vs 6.9 months, respectively).

The Future of EGFR and ALK Inhibition

Patients withEGFRmutations have two available therapies, and patients with ALK translocations also have an approved treatment in crizotinib. Regarding the clinical experience to date with crizotinib, Salgia said, “What we’re seeing are dramatic responses—a lot of times as well-sustained responses—but then there’s an important understanding of these therapeutics in terms of toxicity profile as well. So for crizotinib, we can have nausea, vomiting, and visual changes, but most recently, we’ve been able to identify that you can have changes in endocrine function. For example, testosterone can be low. Sometimes, follicle-stimulating hormone and luteinizing hormone can be affected in women. So what we’re seeing over a long period of time with agents like crizotinib are immediate toxicities but then also long-term toxicities. That’s not uncommon for any medicine.” The dramatic responses to which he referred are the 60.8% of patients in the ongoing phase I trial who had an objective response, including 3 complete responses and 84 partial responses among 143 enrolled patients. The median duration of response was 49.1 weeks (95% CI, 39.3-75.4 weeks).³Although patients withEGFRmutations and ALK translocations now have effective targeted treatment options, there may be opportunities to improve upon the current EGFR options. “Most recently, there’s been some data on a monoclonal antibody to the receptor itself,” said Spigel. “A recent press release revealed that the antibody necitumumab had a survival advantage in lung cancer. That’s going to be a big step forward if it’s true that we have a drug that works differently than erlotinib or afatinib to shut the cancer signaling down from outside the cancer cell using an antibody.” The phase III SQUIRE trial indeed found that patients with stage IV metastatic NSCLC who were treated with necitumumab in combination with gemcitabine and cisplatin in the first-line setting experienced increased OS when compared with chemotherapy alone. If this drug is approved, it could be the first biologic therapy indicated to treat patients with squamous lung cancer.⁴

The EGFR inhibitors are not the only approved targeted therapies in lung cancer that are encountering innovations. Crizotinib itself, which is currently approved only for patients who test positive for the ALK fusion gene, may end up serving multiple purposes. “Initially designed against MET, it’s very important against ALK,” Salgia said. “We also know that ROS1 translocations also respond to crizotinib.”

In fact, patients with ROS1 rearrangements had an objective response rate of 56% in a phase I trial of crizotinib, indicating that ROS1 could be the next target for crizotinib.⁵As Salgia explained, “ALK translocation can occur as EML4-ALK, that’s on chromosome 2, but there can be other partners of ALK which can be gain of function as well that potentially do respond to crizotinib or other small-molecule inhibitors.”

Crizotinib may have some competition in the ALK space as well, as Spigel pointed out, “In the case of ALK, there are what many believe to be much stronger or purer ALK inhibitors in development that look promising, too.” Some of the products in development include LDK378, CH5424802, and AP26113, which inhibits mutant activated forms of ALK and EGFR.^6-8

Other Future Targets

“Many times, crizotinib doesn’t cross the blood-brain barrier, so one can see brain metastasis—either recurrence of brain metastasis or development of brain metastasis,” said Salgia. If one of these investigational products can improve upon crizotinib’s blood-brain barrier penetrance, that could be an important improvement, said Salgia.Even better news for patients with NSCLC is that researchers are continuing to identify and investigate many more targets beyond EGFR, ALK, and ROS-1 that may hopefully someday lead to targeted therapies that cover more of the entire disease population. “I think all of these molecular paths that are abnormal in lung cancer are important,” Salgia said. “We need to continue investigating for the ALK translocation pathways; ROS1 translocation is quite important. We’re seeing a number of patients with RET translocation, as well asBRAFmutations, like the V600E that occurs in melanoma.” Results from a phase II trial of the BRAF inhibitor dabrafenib showed early antitumor activity inBRAF V600Emutation-positive pretreated NSCLC, with an ORR of 54% and the longest duration of response to date being 49 weeks.⁹

In addition to interest in the targets of PI3 kinase, MET, MEK, and Eph receptors, “others are developing strategies to combine EGFR with MET, as an example, as a bi-specific antibody, or other antibodies against various targets, like hepatocyte growth factor,” said Salgia, which would allow more than one target to be treated simultaneously. There is also potential for immunotherapy. “I think the exciting thing is that, all the way from phase I to phase III, there are vaccine trials: the anti-PD-1, the anti-PD-L1. They’re quite investigational but quite exciting,” Salgia said.

Spigel agreed: “Probably the biggest excitement right now across the board in lung cancer is immunotherapy. The promise of it may be that it’s not in use in a targeted population. There are early data from promising drugs that show that patients with the PD-L1 target may benefit most strongly. People talk about immunotherapy being a nontargeted or nonselective approach to fighting cancer, but, in fact, it may turn out that the patients who do the best have PD-L1 as the tumor target.”

References

1. Lee SM, Khan I, Upadhyay S, et al. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial.Lancet Oncol. 2012;13(11):1161-1170.
2. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.J Clin Oncol. 2013;31(27):3327-3334.
3. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012;13(10):1011-1019.
4. Eli Lilly and Company website. Lilly announces phase III necitumumab study meets primary endpoint of overall survival. August 13, 2013. Available at: http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=784772. Accessed October 3, 2013.
5. Ou S-HI, Bang Y-J, Camidge DR, et al. Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC). Presented at: the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.J Clin Oncol. 2013;31(suppl; abstr 8032).
6. Shaw AT, Mehra R, Kim D-W, et al Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. Presented at: the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.J Clin Oncol. 2013;31(suppl; abstr 8010).
7. Nakagawa K, Kiura K, Nishio M, et al. A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: updated safety and efficacy results from AF-001JP. Presented at: the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.J Clin Oncol. 2013;31(suppl; abstr 8033).
8. Camidge DR, Bazhenova L, Salgia R, et al. First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: updated results. Presented at: the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.J Clin Oncol. 2013;31(suppl; abstr 8031).
9. Planchard D, Mazieres J, Riely GJ, et al. Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation—positive non-small cell lung cancer (NSCLC) patients. Presented at: the 2013 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, IL.J Clin Oncol. 2013;31(suppl; abstr 8009).