The Picture Is Finally Changing in Squamous NSCLC

Benjamin P. Levy, MD

Treatment options for patients with squamous non—small cell lung cancer (NSCLC) are expanding rapidly yet the field is still lagging in targeted therapies and curative strategies, according to leading researchers who participated in a recent OncLive Peer Exchange® roundtable.

Additional research is needed not only to define new combination regimens that would benefit patients but also to identify biomarkers that could be targeted in clinical trials, the experts said during the program, entitled “Treating Advanced Squamous Non—Small Cell Lung Cancer.”

“Until recently, little progress had been made in the area of squamous non—small cell lung cancer. Now, with the excitement of recent positive trials and new drugs approved, there are increasing options for patients and the hope of improved outcomes, particularly after failure of chemotherapy,” said Benjamin Levy, MD, who served as moderator for the session.

In less than 18 months, the FDA has approved these drugs for squamous NSCLC: the EGFR inhibitors necitumumab (Portrazza) and afatinib (Gilotrif), the PD-1—targeting immunotherapies nivolumab (Opdivo) and pembrolizumab (Keytruda), and the antiangiogenic antibody ramucirumab (Cyramza).

Defining the Subtype

“That’s unprecedented,” said panel member Paul K. Paik, MD, in reference to the pace of approvals. “And yet, if we look at lung adenocarcinoma as the cousin or the sister or brother [of squamous NSCLC], they’re far better off. And they’re far better off, by and large, because targeted therapy is reality for them.”Squamous cell carcinoma, which comprises approximately 25% to 30% of all lung cancer, is the second-largest histological subtype of NSCLC after adenocarcinoma, according to the American Cancer Society.

Yet distinguishing between squamous and nonsquamous subtypes—and deciding which patients should undergo molecular testing—is not always straightforward, panelists indicated.

To diagnose squamous cell NSCLC, both immunohistochemistry findings and the patient’s clinical presentation are equally important, Levy said.

Edward S. Kim, MD, FACP, said many patients with squamous NSCLC treated at the regionally based community healthcare system where he practices present with a central mass that is causing bronchial constriction.

These patients are often older, in their 70s and 80s, and are active smokers or have recently quit.

Paik agreed with that clinical profile and noted that offering treatment to these patients is a priority. “The main concern for these patients are the symptoms that they’re having and our need to really palliate these things as soon as we can,” he said.

Looking for targetable genetic mutations has been a limited strategy until recently. Squamous NSCLC is a genetically complex disease, Levy said, and the state of knowledge of relevant genetic alterations is not advanced.

Chemotherapy

However, the National Comprehensive Cancer Network (NCCN) now supports limited testing for EGFR mutations and ALK rearrangements in never- smokers with squamous histology, Paik said, as some patients derive benefit from relevant inhibitors. Kim’s advice to the general oncologist is that patients who are never-smokers or have a light smoking history and an atypical presentation should be tested.Chemotherapy doublets have been a backbone of first-line treatment for patients with squamous NSCLC, but these regimens typically consisted of a platinum agent combined with gemcitabine or a taxane until a large phase III study that compared carboplatin with either nab-paclitaxel (Abraxane) or solvent-based paclitaxel.¹

Edward Kim, MD

In all, 1052 patients with untreated stage III-IV disease including 450 participants with squamous NSCLC were randomized to either treatment regimen. Among the squamous population, the nab-paclitaxel regimen demonstrated a 41% overall response rate (ORR) compared with a 24% ORR for participants who had taken the solvent- based paclitaxel combination.

There was a nonsignificant advantage in overall survival (OS) and a more favorable adverse event profile with carboplatin/nab-paclitaxel, Levy said. He said the regimen resulted in lower rates of neuropathy, myalgia, and arthralgia but a higher incidence of neutropenia, anemia, and thrombocytopenia. Another advantage of the nab-paclitaxel regimen is that premedicating with steroids is not needed, Levy said.

Kim noted that more than 150 of the patients were 70 years of age or older and the survival in this group was almost 20 months versus 10 months with the comparator regimen. So, while understanding that several good regimens are available in this setting, he considers carboplatin and nab-paclitaxel to be among the preferred regimens for patients with squamous cell histology.

Paik finds the anemia to be challenging for his patients who are treated with carboplatin/ nab-paclitaxel. Also, few patients can tolerate the regimen at a sustained level. So, he uses a 2-on-1-off or 3-on-1- off schedule, as he thinks a break is needed even while it might decrease efficacy. He notes that 46% of the patients in the trial required a dose reduction in carboplatin and nab-paclitaxel.

In the maintenance setting, there is little to support a choice of therapy in squamous cell NSCLC or even when such treatment is appropriate. But for a patient who has responded well—for example, to a fourth or sixth cycle of a platinum doublet—Paik continues some form of maintenance. He may choose maintenance gemcitabine for patients who started with carboplatin/ gemcitabine.

Paul K. Paik, MD

Monoclonal Antibodies

The panelists are hoping to learn more from the phase III ABOUND trial, in which a maintenance schedule of nab-paclitaxel is being compared with best supportive care in an estimated 540 patients with stage IIIB-IV squamous cell disease who have received induction therapy with nab-paclitaxel and carboplatin.²Bevacizumab is not approved in the squamous cell population, Levy said, but two new monoclonal antibodies—necitumumab and ramucirumab— have been approved specifically for this population, thus providing additional options both in the frontline and chemorefractory settings. Necitumumab is a fully humanized monoclonal antibody against EGFR that has been approved in combination with gemcitabine and cisplatin for the first-line treatment of patients with metastatic squamous NSCLC.

The approval was based on the phase III SQUIRE trial, in which the combination of necitumumab plus gemcitabine and cisplatin improved OS by 1.6 months compared with the chemotherapy agents plus placebo (11.5 mo vs 9.9 mo; P = .012).³

The survival advantage is modest but does represent a step forward, said Paik. He sees necitumumab as a “niche” agent to consider on a case-by-case basis for patients who can handle the side-effect profile of the three-drug regimen. Ramucirumab, a pan-VEGF inhibitor, does not bring the bleeding and toxicity associated with bevacizumab, Kim explained.

It is approved in combination with docetaxel for metastatic NSCLC with disease progression on or after platinum-based chemotherapy based on a 1.4-month median OS improvement compared with docetaxel alone (10.5 mo vs 9.1 mo, respectively) in the phase III REVEL trial.⁴ More than 25% of the 1200-plus patients who participated in the study had squamous histology, and the survival benefit was upheld across this population.

Immunotherapy

Kim said ramucirumab is included in his institution’s pathways as a preferred regimen for squamous cell disease in the second-line and subsequent settings, and prefers it to single-agent docetaxel, erlotinib, vinorelbine, or gemcitabine.Nivolumab and pembrolizumab have been “complete game changers” for the treatment of all NSCLC histologies including squamous cell disease, Levy said, and he suggests that every appropriate candidate receive this therapy whether in a clinical trial or as standard of care. They bring adverse events, however, and oncologists must learn how to manage them.

CheckMate 017⁵ compared nivolumab with docetaxel in a chemorefractory, squamous cell population, Levy said. There was improvement in response rate, progression free survival, and OS; the risk of death was 41% lower with nivolumab versus docetaxel (HR = 0.59; P <.001). Additionally, the grade 3/4 AEs were more manageable in the nivolumab arm than the docetaxel arm.

Kim agreed that these drugs have made a major clinical impact but said the 9.2-month median OS seen with nivolumab in the CheckMate 017 trial is not as dramatic as findings for EGFR inhibitors in other NSCLC settings. He said the favorable side effect profile is what makes them more attractive that a cytotoxic agent and why he considers them to be game changers.

Although the response rate is 20%, some responses are quite durable, with median durations of response extending over a year, Levy noted. Kim pointed out the need for biomarkers to better identify the patients who are more likely to respond.

Tyrosine Kinase Inhibitors

Paik said he uses nivolumab frequently and considers it the current de facto standard in the second-line setting for appropriate patients.Although data on the efficacy of using tyrosine kinase inhibitors (TKIs) targeting EGFR in patients whose tumors do not harbor the mutation has proved to be a controversial question, findings concerning the newer generation TKI afatinib complicate that thinking.

Afatanib, an irreversible EGFR inhibitor, gained approval in mid-April as a treatment for patients with advanced squamous NSCLC following progression on platinum-based chemotherapy. The approval was based on the phase III LUX-Lung 8 study, in which afatinib reduced the risk of death by 19% and disease progression by 18% compared with erlotinib.⁶

In squamous cell carcinoma, Levy said he has been using TKIs as a second- or third-line therapy patients who are not enriched for the mutation and who can’t tolerate chemotherapy. However, he noted that the data are conflicting and that newer options have bumped TKIs further down the lines of treatment.

Paik noted that about 6% of the some of the nearly 800 patients who participated in the LUXLung 8 trial had EGFR mutations and wondered whether that fueled the benefit for the drug in the entire population. He said more research must be conducted.

Similarly, Kim described the patient population most likely to benefit from a TKI for most patients with squamous NSCLC. He said patients with poor performance status who are not able to receive chemotherapy and are getting close to hospice care are the subset that would most likely be candidates for TKIs.

References

1. Socinski MA, Okamoto I, Hon JK, et al. Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer. Ann Oncol. 2013;24(9): 2390-2396.
2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identifier: NCT02027428.
3. Thatcher N, Hirsch FR, Luft AV, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015;16(7):763—774.
4. Pérol M, Ciuleanu TE, Arrieta O, et al. REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy. J Clin Oncol. 2014;32:5s (suppl; abstr LBA8006).
5. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non—small-cell lung cancer. N Engl J Med. 2015;373(2):123-35.
6. Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as secondline treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897-907.