Targeted Therapy for Advanced Squamous Cell Lung Cancer

Abstract

Squamous cell lung cancer is a unique subset of non-small cell lung cancer (NSCLC), with an aggressive phenotype. Unlike adenocarcinoma of the lung, where genomic profiling is part of the standard of care, and targeted therapies are routinely used, there are limited data on the activity and efficacy of targeted agents for this subset of patients. Squamous cell cancer also offers distinct therapeutic challenges by virtue of presentation in older patients, its physical location in the chest, pattern of metastasis and association with comorbidities that can compromise treatment delivery and exacerbate toxicity. Over the last decade, we have made tremendous progress in our understanding of the biology and molecular characteristics of this disease. Novel targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab have yielded improvements in survival that are also seen in squamous cell NSCLC. Additionally, with the availability of genomic sequencing, we are now able to offer precise targeting for relevant actionable targets. Herein, we review the currently available and approved therapeutic agents for the management of metastatic squamous cell NSCLC and clinical trials focusing on targeted therapy.

Introduction

Lung cancer remains the most common cause of cancer related mortality in the United States.¹Of all lung cancer cases, over 85% are classified as non-small cell lung cancer (NSCLC), with squamous cell carcinoma (SqCC) comprising approximately 30%. SqCC, once the most common subtype of NSCLC, has declined in incidence over the past 2 decades, mainly related to an overall decline in the incidence of smoking patterns and changes in cigarette filters, which facilitate distal delivery of tobacco smoke in the lungs.²The latter has contributed to an increase in incidence of adenocarcinoma, which accounts for the majority of the patients with NSCLC.³Despite the declining incidence, lung SqCC remains a common malignancy, accounting for approximately 85,000 new cases in the USA each year and over 400,000 worldwide. SqCC poses many therapeutic challenges related to patient demographics, tumor characteristics and tumor biology. Patients tend to be older, with a high incidence of smoking, and a higher incidence of comorbidities, including low pulmonary reserve and presence of COPD.^3,4Additionally, SqCC often involves the central airways, and the location of these tumors in proximity to large blood vessels can present treatment challenges, including bleeding and hemoptysis, which, in turn, can contraindicate the use of certain therapeutic agents.⁴

With the availability of widespread genomic sequencing, and the introduction of specific targeted agents for subsets of patients with adenocarcinoma, such as those with activating mutations in the epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene rearrangements, survival for patients with non-squamous metastatic NSCLC has significantly improved.^5-7At the same time, therapeutic progress in squamous cell lung cancer has been relatively slow, with relative stagnation of survival numbers, in the 9—11 month range, without substantial improvement up until very recently.8 With the exception of the newly approved necitumumab, there have been no other US Food and Drug Administration (FDA) approvals specifically for SqCC of the lung. Treatment for SqCC of the lung remains an unmet need, and novel treatment strategies are needed, including specific targeted therapies, which would provide clinically meaningful outcomes without adversely affecting quality of life.

Recently, molecular genotyping has led to the application of targeted agents for mutations prevalent in SqCC.⁹This overview of the targeted treatments of squamous cell lung carcinoma highlights these recent molecular advances and discusses the potential role of newer molecular agents currently being evaluated for the treatment of advanced SqCC.

First Line Therapy of Advanced SqCC

Platinum-based doublets are the cornerstone of firstline systemic palliative therapy for advanced SqCC. Earlier trials conducted with either a cisplatin or carboplatin- based regimen utilizing different platinum partners, namely paclitaxel, gemcitabine, or docetaxel did not show any significant difference in survival.10 More recently, survival benefit was observed in advanced SqCC for gemcitabine-cisplatin versus pemetrexedcisplatin (n = 473; 10.8 v 9.4 months, respectively) in a phase III randomized clinical trial.^11,12Based on these results, a platinum agent plus either gemcitabine or a taxane remains the most frequently used first-line combination, with the selection of agents generally based on toxicity and pre-existing medical issues. Nabpaclitaxel is another option for treatment of patients with advanced SqCC.^13,14In a subset analysis of a phase III study (n = 1052, first-line nab-paclitaxel-carboplatin combination demonstrated a significant improvement in response rate versus paclitaxel-carboplatin (41% v 24%;P<.001). Although the improvement in response rate did not translate into significant survival benefit in either SqCC (10.7 v 9.5 months; hazard ratio [HR], 0.89) or non-squamous NSCLC (13.1 v 13.0 months; HR, 0.95), nab-paclitaxel plus a platinum agent, generally carboplatin, remains a viable first-line treatment option for patients with SqCC that may offer some advantages, mainly lower incidence of peripheral neuropathy, fewer infusion reactions, and shorter infusion time.¹⁴

Additionally, necitumumab, a second-generation monoclonal antibody targeting EGFR, was recently approved (November 2015) in combination with gemcitabine- cisplatin for the first-line treatment of metastatic SqCC. This approval came about after a demonstration of superior survival with combination therapy compared to chemotherapy alone (11.5 v 9.9 months; HR, 0.84; 95% CI, 0.74 to 0.96;P= .01), progression-free survival (PFS) (5.7 v 5.5 months; HR, 0.85; 95% CI, 0.74 to 0.98;P=.02), and disease control rate (82% v 77%;P=.043).¹⁵This was one of the first trials to show superior survival for a new agent when combined with chemotherapy versus chemotherapy alone in lung SqCC. The necitumumab safety profile is consistent with an EGFR antibody in combination with chemotherapy, with venous thromboembolic events more common and increased incidences of grade >3 skin reactions and hypomagnesemia.¹⁵

Second and Subsequent Line Therapy for SqCC

The paradigm of second-line therapy for SqCC has changed significantly with the approval of nivolumab and pembrolizumab in March 2015 and October 2015, respectively. These checkpoint inhibitors that block the programmed cell death protein (PD-1) pathway, restore immune system function, and allow T-cells to function appropriately against tumors. The approvals of the anti- PD-1 agent nivolumab for second-line treatment of advanced SqCC was based on the results of the phase III Checkmate 017 study of nivolumab versus docetaxel (n = 272).^16,17Patients who received nivolumab had significantly longer median overall survival versus patients who received docetaxel (9.2 v 6.0 months; HR, 0.59; 95% CI, 0.44 to 0.79;P<.001), increased median PFS (3.5 v 2.8 months; HR for death or disease progression, 0.62; 95% CI, 0.47 to 0.81;P<.001), and increased response rate (20% v 9%;P= .008). The 1-year survival rates were 42% and 24%, respectively. Median duration of response was not reached in the nivolumab group versus 8.4 months in the docetaxel group. Grade 3 or 4 treatment-related adverse events were reported less frequently with nivolumab compared with docetaxel (7% v 55%). In an exploratory analysis in a limited number of patients, which used low cut-offs for PD-L1 expression, the OS and PFS benefits with nivolumab were observed regardless of tumor PD-L1 expression levels. Another anti-PD-1 agent, pembrolizumab, received accelerated approval in the United States for second-line treatment of patients with advanced NSCLC, including SqCC, whose tumors express PD-L1, based on a subgroup analysis of patients in the KEYNOTE-001 study with a PD-L1 expression tumor proportion score (TPS) &ge;50% (n = 61) for whom a response rate of 41% and long duration of response was observed.18 Additionally, in the second-line Phase II/III KEYNOTE-010 study (n = 1034), pembrolizumab demonstrated longer OS versus docetaxel in patients with both PD-L1 TPS &ge;50% and TPS &ge;1% regardless of histology.¹⁹This benefit was also seen for the SqCC subset with a HR of 0.74 (CI 0.50-1.09). Other anti-PD-1 and anti-PD-L1 agents, such as atezolizumab and durvalumab, are in phase III development for advanced NSCLC, including SqCC.

Other agents such as docetaxel or erlotinib are considered reasonable therapeutic options, but these are not specifically approved for SqCC. Ramicirumab, a VEGFR2-targeted monoclonal antibody, was evaluated in a phase III randomized trial (REVEL, n = 1253), in combination with docetaxel in patients with advanced NSCLC progressing after primary platinum-based chemotherapy, regardless of tumor histology. Ramucirumab plus docetaxel demonstrated improved median OS versus docetaxel alone in the overall population (10.5 v 9.1 months; HR, 0.86; 95% CI, 0.75 to 0.98;P= .023).20 Comparable, but non-significant, OS benefits were observed in the SqCC subgroup (n = 328 [26%]; 9.5 v 8.2 months; HR, 0.88; 95% CI, 0.69 to 1.13). This is the only anti-angiogenic drug to have an indication for SqCC.

Targeted Therapy for SqCC

Until recently, little was known about the genomics of SqCC. With the availability of gene sequencing, and comprehensive genomic surveys, our understanding of the mutational profile of SqCC has vastly improved.⁹Progress has been slow, and still lags behind that of adenocarcinoma. Genetic alterations within lung adenocarcinomas and SqCC are distinct; for example, there is a paucity of KRAS and EGFR mutations in SqCC. SqCC also tend to be genetically more complex, with a high frequency of complex mutations, and amplification of multiple receptors. We have learned that lung SqCC are characterized by a high overall mutational burden, at a rate of 8.1 mutations per megabase.⁹Almost all SqCC display somatic mutations of TP53.

The most common alterations were seen in pathways associated with tumor growth, proliferation, and survival. Additionally, fibroblast growth factor receptor-1 (FGFR1) amplification (approximately 25% of SqCC, using a 3.5 fold amplification, seen in about 5%), discoidin domain receptor-2 (DDR2) mutations (~ 4%) are attractive, actionable targets.

The Cancer Genome Atlas Project (TCGA) extensively profiled 178 SqCC tumor specimens for genomic alterations by whole exome sequencing, mRNA sequencing, and other techniques to comprehensively define the genomic landscape of SqCC. Genes such asCDKN2A/ RB1, NFE2L2/KEAP1/CUL3, PI3K/AKT, and SOX2/ TP63/NOTCH1signaling pathways were also commonly altered.⁹In another recent study, comprehensive genomic analysis in resected SqCC patients (n=157) revealed somatic mutations in 73.9% of cases, withTP53(56.1%),CDKN2A(8.9%),PIK3CA(8.9%),KRAS(4.5%), andEGFR(3.2%). Gene copy number alterations were identified in 75.8% of cases, includingSOX2amplification (31.2%),CDKN2Adeletion (21.7%),PTENdeletion (16.6%),FGFR1amplification (15.9%),EGFRamplification (14.0%),CCND1amplification (14.0%),HER2amplification (9.6%), andPDGFRAamplification (7.6%). Positive expression ofVEGFR2and PD-L1 and loss of PTEN expression were observed in 80.5%, 47.2%, and 42.7% of cases, respectively.²¹

Due to the genetic diversity and lack of clear oncogenic drivers in this disease, there is a need to develop clinical trials solely focused on SqCC that can evaluate single agent and combination targeted therapies.

The Lung-MAP (clinical principal investigators [PIs]: Drs. Vali Papadimitrakopoulou, Roy Herbst, David Gandara; statistical PI Mary W. Redman) is a master multi study protocol that incorporates genomic testing of tumors through a next-generation sequencing (NGS) platform (Foundation Medicine) for patients with SqCC after progression on first-line therapy. This protocol, led by SWOG, represents a partnership engaging the National Cancer Institute (NCI) and its Thoracic Malignancies Steering Committee (TMSC), the Foundation of the NIH (FNIH), the pharmaceutical industry, advocacy groups such as Friends of Cancer Research (FOCR), and the Federal Drug Administration (FDA). It is the most comprehensive and collaborative lung cancer clinical trial active in the United States, with the goal to identify safe and effective regimens that match predictive biomarkers with targeted drugs. After genomic testing, patients are assigned to one of several substudies, each evaluating an experimental targeted therapy, based on identification of candidate predictive biomarkers associated with each substudy. These substudies are being conducted as single-arm phase II studies, without randomization to docetaxel, making it more attractive for patients with specific targetable mutations. The primary objective for these studies is overall response rate. If the objective response rate observed in the phase II study is judged sufficient the study will proceed into a phase III trial in which patients will be randomized to biomarker-driven targeted therapy compared to standard-of-care therapy. Each substudy will function autonomously and will open and close independent of the other substudies. Additionally, it offers patients both targeted and immunotherapy treatments, all under the umbrella master protocol design. Immunotherapy arms are being offered to patients without matching genetic alteration, and the current trial builds on the rapidly changing standard of care. The design of Lung-MAP allows for the addition of new substudies evaluating either new biomarker/drug pairs or new targeted therapies.

FIGURE 1

displays the overall schema for Lung- MAP and the initial drug targets being tested,PI3K, FGFR, CDK 4/6. Patients who are not candidates for biomarker-driven substudies, may enroll on the nonmatch substudy and receive therapy with nivolumab or combination nivolumab and ipilimumab. Rapid turnaround time of NGS screening results, within 16 days, allows real time assignment into the appropriate substudy. Lung-MAP is poised to change the way new drugs are developed in lung cancer, and the approach will be extrapolated into other settings in lung cancer and into other tumor types as well. Similar efforts are underway in other countries as well, for example, the SAFIR02_LUNG trial, being conducted in France (NCT02117167), and National Lung Matrix Trial, UK (NCT02664935). These are open-label randomized phase II trials, using high throughput genome analysis as a therapeutic decision tool, aimed at comparing a targeted treatment administered according to the identified molecular anomalies of the tumor with standardof- care therapy.

The Phosphoinositide 3-Kinase Pathway

Phosphoinositide 3-kinase, (PI3K) is a lipid kinase involved in tumor cell proliferation, survival, and migration upon activation by growth factor receptors and integrins.PI3Kcatalyzes the phosphorylation of phosphatidylinositol- 4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), a second messenger involved in the phosphorylation of AKT and associated proteins in the AKT-mTOR pathway. Activating and transforming mutations, as well as amplification, in the p110&alpha; subunit of PI3K are commonly found in solid and hematological tumors. In addition, the PI3K-AKT pathway is activated in numerous types of cancer by receptor tyrosine kinase signaling, the loss of the phosphatase tensin homolog (PTEN), or RAS mutations.^22,23GDC-0032 (Taselisib) is an oral, potent, selective small molecule inhibitor of Class 1PI3Kthat has established safety profile in phase I studies, with partial responses seen in dose escalation in patients withPIK3CAmutant NSCLC tumors.

Cyclin Dependent Kinase Amplification

The cyclin-dependent kinases (CDKs) form heterodimeric protein complexes with cyclins and play key roles in cell cycle progression and transcription regulation. Squamous cell carcinoma of the lung has been demonstrated to have CCND1 alterations, and CDK4/6 amplifications.9 Palbociclib, an orally active pyridopyrimidine, is a potent and highly selective reversible inhibitor of cyclin-dependent kinase (CDK) 4 and CDK6. The compound prevents cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase, as demonstrated in laboratory models and early clinical trials. Palbociclib has been tested in a phase I dose escalation study, with a significant proportion of patients with stable disease observed. It has been approved in metastatic breast cancer for treatment of hormone positive disease.^24-27

FGFR Mutation/Amplification

There is a strong preclinical rationale for testing the activity of AZD4547 in patients with squamous lung cancer harboring fibroblast growth factor receptor (FGFR) aberrations. Amplifications of theFGFR1are associated with NSCLC and have been described in up to 20% of squamous cell lung cancers with mutations and fusions in FGFR 2 and 3 occurring at a lower incidence (each <4%).^21,28AZD4547 is a potent and selective inhibitor of the FGFR 1, 2, and 3 receptor tyrosine kinases (enzyme and cellular phosphorylation endpoints), and has a significantly lower potency for inhibition of FGFR4, insulin-like growth factor 1 receptor (IGF1R), and kinase insert domain receptor (KDR). Inhibition of FGFR-mediated signaling can result in an anti-proliferative and/or pro-apoptotic activity, may have an anti-angiogenic effect, and may play a role in resistance to vascular endothelial growth factor (VEGF) inhibitor therapy. In a small clinical study in squamous NSCLC there was at least 1 PR in the 14 patients treated with AZD4547. The patient carried an FGFR1 amplification.²⁹

Other Targets

Other targets with active agents that are under investigation includePDGFR(NCT02109016),AKTpathway, andMETamplification. Specific inhibitors targeting TORC1/2 are under active development (NCT02417701), and combination therapies with FGFR inhibition +MEKinhibition (selumetinib) are being actively explored (NCT02583542).

Conclusion

Squamous cell lung cancer remains a therapeutic challenge because of its presentation, patient characteristics, disease location, and higher incidence of comorbidities. While we have made significant advances in the therapy of SqCC, including approval of immunotherapies, there remains a significant need for development of targeted modalities, driven by our improved understanding of genomics of SqCC.

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