Treating Squamous vs Nonsquamous Disease

Nathan Pennell, MD, PhD

The Standard of Care Has Not Changed

The addition of bevacizumab, erlotinib, afatinib, and crizotinib to the treatment arsenal for non-small cell lung cancer (NSCLC) has been a major advance beyond the standard cytotoxic options in the treatment of this disease. However, there is a large imbalance within tumor types. These advances really apply only to patients with nonsquamous disease (lung adenocarcinoma), while patients with squamous carcinoma remain stuck in the era before targeted therapies.“In a way we’ve been very fortunate in the nonsquamous patients, because they have a very high rate of having a single, what we call a driver mutation, such as theEGFRmutation orALK, but there are other ones, includingROS1andRET. There are a dozen or more of these that seem to be present in the majority of patients with nonsquamous, non-small cell lung cancer,” said Nathan Pennell, MD, PhD, assistant professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute. “When you look at squamous cell carcinoma, it’s a much more complicated disease, probably because of the influence of tobacco in most of these patients that causes an extremely high rate of mutations and other genetic changes. So you don’t get the same rate of these single driver mutations. What you more commonly see are problems with specific intracellular signaling pathways, such as the PI3 kinase signaling pathway, so you can see mutations in squamous cell carcinoma in about 15% of the patients in thePI3kinase gene,” he said.

Dr. Belani on the Treatment of Lung Cancer Subgroups

Belani is the Deputy Director at Penn State Hershey Cancer Institute.

Because lung adenocarcinoma is a less complicated form of the disease that tends to derive from those single driver mutations, treatments have been developed that effectively treat those mutations or genetic rearrangements. And because these treatments exist, all patients with lung adenocarcinoma should be tested for these genetic abnormalities to discover whether or not they are candidates for treatment. The experience is different for patients with squamous carcinoma.

“The big difference is, if you have lung adenocarcinoma, you’re going to have molecular genotyping up front, which may determine the first therapy you get. In squamous, you get chemotherapy up front, and, if you’re going to go on a trial, which is a minority of patients, it will be in second line,” said Peter Hammerman, MD, PhD, medical oncologist at the Dana-Farber Cancer Institute and Lowe Center for Thoracic Oncology, in Boston, as well as assistant professor at Harvard Medical School in the Department of Medical Oncology, Division of Molecular and Cellular Oncology. Therefore, he continued, “in squamous, there’s no standard of care for upfront genotyping. Patients receive first-line chemotherapy, no different than you would have 10 years ago for the most part.”

Identifying New Targets in Squamous Disease

Because of the complex array of genetic abnormalities that could be associated with squamous disease, there is much research to be done to find new targets for therapy to improve treatment options for these patients. “We have a long way to go to get where we are in the nonsquamous patients at identifying targets,” Pennell said.

One area that has been identified as a potential target in nonsquamous disease so far is the PI3 kinase pathway. Up to 9% of squamous cell lung cancers involvePI3kinase mutations.¹“There are a lot of PI3 kinase alterations in squamous cell cancer. There’s probably going to be a role for PI3 kinase inhibitors used in some fashion, perhaps not as monotherapy in squamous disease just because of the prevalence of alterations in squamous disease,” said Hammerman. There are a number of different potential targets within the PI3 kinase family, including phosphatase and TENsin homolog (PTEN).²

Clinical Pearls

• All patients with lung adenocarcinoma should be tested forEGFRmutations andALKrearrangements, regardless of patient characteristics.
• If a biopsy shows mixed histologies, including both adenocarcinoma and squamous carcinoma, or if the biopsy was too small to be conclusive, then molecular testing should be performed.
• Testing for biomarkers in addition toEGFRmutations andALKrearrangements can provide valuable information toward future targeted therapies, as well as clinical trial eligibility.
• There are many second-generation EGFR and ALK inhibitors in development, as well as agents aimed at purely investigational targets.
• Immunotherapy using PD-1 blockade also holds promise, especially for the squamous carcinoma population, which is in great need of treatment advances.
• All patients with lung squamous carcinoma should be considered for a clinical trial to gather data on potential treatment options for the future.

“Another large number of patients have inactivation of something called PTEN, which tends to activate that PI3 kinase pathway, and there are a number of targeted agents that are being designed to target that pathway, either at the PI3 kinase level, at the Akt level, at the mTOR level, and some of them are combination inhibitors of both PI3 kinase and mTOR,” Pennell said. “All of these are in very early-stage development, and so none of them really has yet been shown to be particularly effective in that group, but it certainly is a very promising area of investigation.”

Hammerman has his eye on another PI3 kinase target. “The most advanced kinase inhibitors in squamous are agents which target fibroblast growth factor receptors (FGFRs),” he said. “There has been some phase I activity there, and I suspect we’ll see phase II activity, but that’s still hypothetical.”FGFR1amplification is seen in 16% to 22% of patients with squamous carcinoma.^3-5“There are probably somewhere between 10 and 20 FGFR inhibitors of reasonable quality. Most of the trials to date have targetedFGFR1amplification. That is a biomarker that, for people who are used to erlotinib-like responses, it’s not there. The response rates we’ve seen so far have been more in the 20% to 30% range, which is better than chemotherapy, but we still have quite some way to go there,” said Hammerman.

Another potential target under investigation is discoidin domain receptor 2 (DDR2). Oncogenic mutations in theDDR2kinase gene were found in 3.8% of 222 lung squamous cell samples.⁶Dasatinib is a multitargeted kinase inhibitor that blocks DDR2. A phase I trial of dasatinib therapy in an unselected cohort of patients with NSCLC needed to be terminated due to pulmonary toxicity, pointing to a need for caution when using dasatinib for lung cancer in patients with prior thoracic radiation.⁷Nevertheless, there have been positive preclinical findings with dasatinib, as well as a report of a patient with squamous cell cancer with noEGFRmutation who had aS768Rmutation and responded to a combination of dasatinib and erlotinib on a clinical trial.^6,8

In addition, a more immunologically driven target in squamous carcinoma is programmed death protein-1 (PD-1). “There’s a lot of interest, particularly in squamous, given the lack of other options, in putting patients on PD-1 trials,” Hammerman said. Investigators in Brazil confirmed the involvement of PD-1 in the development of squamous cell carcinomas, and that blocking PD-1 can ameliorate the T-cell dysfunction that can be caused by PD-1.⁹A monoclonal antibody targeting PD-1 called nivolumab produced objective responses in 6 of 18 (33%) patients with squamous lung cancer tumors in a phase I clinical trial.¹⁰

The Future Lies in Clinical Trials

Now that there are several targets to investigate in squamous disease, the challenge becomes finding enough patients to participate in trials, as squamous cell carcinomas comprise roughly 25% to 30% of all lung cancers.11 “It’s awfully hard to accrue a squamous trial at one center. There just aren’t as many patients as there are in adenocarcinoma,” Hammerman said. In addition, he said, “A lot of centers are not up and running with molecular diagnostics for squamous. Insurance isn’t paying for them yet, so there’s not really a national infrastructure to do good squamous trials, but that’s hopefully changing. There’s been some interest at NCI [National Cancer Institute] and cooperative groups in changing that, but it has been challenging to accrue squamous trials.”

Despite the challenges, clinical trials are really the best way to improve the options for squamous disease. “Unfortunately for now, I think every patient with squamous cell carcinoma, whether first-line or after they fail first-line, should be enrolled on a clinical trial, because we really do have a lot out there being investigated. But unfortunately, there’s nothing really exciting that’s been approved for squamous cell carcinoma in probably over a decade,” Pennell said.

These investigations do carry hope, though, as Hammerman noted. “There now are biomarkers for squamous disease. There now are trials for squamous disease. I think before, people didn’t even really think of testing patients and putting them on trials or referring them to centers where that’s possible. I think now there’s an increased opportunity to explore targeted therapy in squamous patients, and we need to get these trials done.”

References

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2. Mantripragada K, Khurshid H. Targeting genomic alterations in squamous cell lung cancer.Front Oncol. 2013;3:195.
3. Heist RS, Mino-Kenudson M, Sequist LV, et al. FGFR1 amplification in squamous cell carcinoma of the lung.J Thorac Oncol. 2012;7(12):1775-1780.
4. Dutt A, Ramos AH, Hammerman PS, et al. Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer.PLoS ONE. 2011;6(6):e20351.
5. Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer.Sci Transl Med. 2010;2(62):62ra93.
6. Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.Cancer Discov. 2011;1:78-89.
7. Khurshid H, Dipetrillo T, Ng T, et al. A phase I study of dasatinib with concurrent chemoradiation for stage III non-small cell lung cancer.Front Oncol. 2012;2:56.
8. Haura EB, Tanvetyanon T, Chiappori A, et al. Phase I/II study of the Src inhibitor dasatinib in combination with erlotinib in advanced non-small-cell lung cancer.J Clin Oncol. 2010;28(8):1387-1394.
9. Belai EB, de Oliveira CE, Gasparoto TH, et al. PD1 blockage delays murine squamous cell carcinoma development [published online ahead of print September 12, 2013].Carcinogenesis. 2013.
10. Topalian SL, Hodi, FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti—PD-1 antibody in cancer.N Engl J Med. 2012;366(26):2443-2454.
11. American Cancer Society. Lung cancer (non-small cell). http://www.cancer.org/cancer/lungcancer-non-smallcell/index. Accessed October 3, 2013.