Checkpoint Inhibitors in Squamous Non-Small Cell Lung Cancer (NSCLC)

Checkpoint inhibitors have demonstrated efficacy in squamous NSCLC with tolerable toxicity profile. They are used as a monotherapy, in combination with chemotherapy or following chemo-radiotherapy as a first line, second line or consolidation therapy. As a first line, Pembrolizumab improves outcome (PFS) as a monotherapy in patients with PD-L1 expression of ≥ 50% (HR; 0.35). When used with chemotherapy, it improves PFS (HR; 0.56) irrespective of PD-L1 expression level. Nivolumab also improves PFS (HR; 0.62), when used as a second line for those progressing with chemotherapy. Durvalumab improves PFS (HR; 0.68) when used following chemo-radio therapy as a consolidation therapy.


Introduction
Lung cancer remains the most common cancer diagnosis and the leading cause of cancer-related deaths, with approximately 1.8 million new cases and 1.59 million deaths accounting every year worldwide [1]. Non-small cell lung cancer (NSCLC) covers the 80% of these lung cancer cases and mainly includes two large histological subsets, adenocarcinoma and squamous non-small cell lung cancer (Sq NSCLC) Clinically also Sq NSCLC differs remarkably from adenocarcinoma as it is located more centrally, and arise segmentally involving lobar or main bronchi and often having central cavitation. There is difference in molecular markers also. Based on molecular changes targeted therapies have been developed for subtypes of adenocarcinoma of lung e.g. EGFR inhibitors. Their use is associated with improved outcome with better tolerability. However, such advances have not taken place in management of Sq NSCLC and the conventional platinum-based chemotherapy remained the first line and second line option for patients with Sq NSCLC till recently. Necitumab approved for Sq NSCLC did not became popular due to its side effect profile and limited benefit [2]. Introduction and development of checkpoint inhibitors has changed the management of Sq NSCLC. Checkpoint inhibitors have been evaluated in NSCLC in whole spectrum ranging from neoadjuvant to third line settings and has been indicated as first line, second line and consolidation therapy [2,3]. In this review, information related to use of check point inhibitor in the treatment of Sq NSCLC is presented. Pembrolizumab (Keynote-407), Atezolizumab (IMpower-131) have been evaluated with chemotherapy in first line management of advanced Sq NSCLC. Nivolumab (CheckMate 017) has been evaluated in second line management of Sq NSCLC as monotherapy. Rest of studies evaluated checkpoint inhibitors in management of Sq NSCLC as a subgroup in main study. They are also included in this review.

Checkpoint Inhibitors as a Neoadjuvant Therapy
Nivolumab has been evaluated in neoadjuvant setting prior surgical resection in 21 patients [4]. All patients received two doses of 3mg/kg of nivolumab, two weeks apart. Of 6 patients included in the study, two had pathological response. This was associated with lymphocytic infiltration of tumor. There was higher frequency of T-cell clones that were shared between intratumoral and peripheral compartments and a higher clonality of the T-cell population. Many of these clones were not detected in the peripheral blood before treatment. Tumor response to nivolumab was also related to tumor mutation burden.

Checkpoint Inhibitors as a First Line Therapy
Checkpoint inhibitors have been evaluated as a monotherapy in patients having PD-L1 expression Tumor Proportion Score (TPS) ≥ 50% as well as in patients with high mutation burden. In all, the majority of the Task Force recommended pembrolizumab monotherapy for patients with Sq NSCLC and PD-L1 TPS ≥ 50%, based on Level A evidence. For patients with squamous histology and PD-L1 TPS < 50%, the Task Force unanimously recommended combination pembrolizumab + chemotherapy pending FDA approval, based on Level A evidence.

Keynote-024 [5]
305 patients, were randomized to receive pembrolizumab (200 mg fixed dose every 3 weeks) or investigator's choice of platinum-based chemotherapy. Patients eligible for EGFR inhibitors or ALK inhibitors were excluded. It included 56 with Sq NSCLC histology 18% in each arm) expressing more than 50% PD-L1. Progression Free Survival (PFS) was significantly better in the Sq NSCLC subpopulation receiving immunotherapy compared to chemotherapy [Hazard Ratio (HR) =0.35, 95% Confidence Interval (CI): 0.17-0.71]. This was also better than the improvement seen with pembrolizumab in whole group [HR 0.5 for group vs 0.35 for Sq NSCLC]. Similar to other immunotherapies, pembrolizumab appeared fewer toxicities compared to chemotherapy arm (any grade 73.4% vs. 90.0% and grade 3/4 26.6% vs. 53.3%, respectively). Most immunotherapy-related adverse events (AEs) were early detected at grade 1 or 2 and well managed with no recorded immunotherapy-related deaths.

Keynote-042 [6]
1274 patients, were randomized to receive pembrolizumab (200 mg fixed dose every 3 weeks) or investigator's choice of platinum-based chemotherapy. Patients eligible for EGFR inhibitors or ALK inhibitors were excluded. It included 492 patients with Sq NSCLC histology of which 243 received pembrolizumab. Overall Survival (OS) was significantly better in the Sq NSCLC subpopulation receiving immunotherapy compared to chemotherapy [HR =0.75, 95% CI: 0.60-0.93]. This was also better than the improvement seen with pembrolizumab in non-squamous NSCLC [HR 0.86; 95% CI: 0.72-1.03].

Nivolumab
Nivolumab has been evaluated as first line therapy in checkmate 227 and checkmate 026.

Checkmate227 [7]
Combination of checkpoint inhibitors (Nivolumab + Iplimumab) was evaluated against chemotherapy in patients with advanced NSCLC (squamous and non-squamous) in the CheckMate227 study in first line setting. All patients had high tumor mutational burden [more than 10]. It had 100 patients with Sq NSCLC and 199 patients with non-squamous NSCLC. HR for disease progression or death for squamous NSCLC was 0.63 (95% CI, 0.39-1.04). It was lower (0.63 vs 0.55) compared to non-squamous NSCLC as well as compared to whole group [0.63 vs 0.58]. Survival data is immature.

Combination with Chemotherapy
Checkpoint inhibitors have been evaluated with chemotherapy in management of squamous as well as non-squamous NSCLC.
For Sq NSCLC, Pembrolizumab as well as atezolizumab has been evaluated in combination with paclitaxel containing platinum doublet. Both are associated with improved outcome.

Pembrolizumab [9]
Pembrolizumab in combination with carboplatin + nabpaclitaxel/paclitaxel as first-line treatment was evaluated in

Nivolumab [11]
CheckMate227 also evaluated nivolumab + chemotherapy against chemotherapy as well as against nivolumab + iplimumab in 550 patients. It included 49 patients randomised to receive nivolumab + chemotherapy or chemotherapy. PFS with Nivolumab + CT was found to be little better (HR=0.92) which was not significant. Patients with non-squamous NSCLC did better (HR=0.68) ( Table 2).

Checkpoint inhibitors as a Consolidation therapy
Checkpoint inhibitors has been evaluated as a consolidation therapy following chemoradiotherapy.

Durvalumab [12]
In a PACIFIC study, 713 patients with stage III NSCLC nonprogressing after at least two cycles of chemo-radiation were randomized to receive durvalumab (n=476) at 10 mg/kg or placebo (273), every other week, for up to a year as consolidation/ maintenance therapy following chemo-radiation. It included 326 patients with Squamous NSCLC. 224 patients with squamous NSCLC received durvalumab and 102 received placebo. Durvalumab was associated improved progression free survival. The hazard ratio was 0.45 (0.33-0.59) for adenocarcinoma and 0.68 (0.50-0.92) for squamous NSCLC. Thus Durvalumab provides better outcome for adenocarcinoma compared to Squamous NSCLC. The safety profile of durvalumab was similar to placebo regarding toxicities greater than grade 3 (29.9% vs. 26.1%, and the most commonly observed pneumonia presented in 4.4% vs. 3.8% of cases, respectively).

Checkpoint Inhibitors as a Second Line Therapy
Checkpoint inhibitors (nivolumab, pembrolizumab and atezolizumab) had their first approval in management of NSCLC as a second line therapy based on improvement in OS. They were evaluated as a monotherapy against docetaxel as a chemotherapy. Improvement in OS was not related to changes in PFS. Surprisingly, all three checkpoint inhibitors were found to provide less benefit in squamous NSCLC compared to advantage seen in non-squamous NSCLC. Atezolizumab was found inferior to Docetaxel in Sq NSCLC subgroup.

Nivolumab
Nivolumab was the first immunotherapy agent that received approval for the second line approach of Sq NSCLC, based on the results of CheckMate017. This phase III, randomized trial exclusively enrolled 272 patients with Sq NSCLC and compared nivolumab versus docetaxel in the second line setting. All enrolled patient had received a platinum doublet as a first line [14]. This phase III, randomized trial resulted in a statistically significant improvement of ORR (20% versus 9%). Nivolumab improved median OS by 3.2 months (9.2 vs. 6.0 months; HR 0.59; 95% CI: 0.44-0.79; p < 0.001) [14]. This was also associated with increased survival of 18% [42% vs 24%] at one year and 16% [24% vs 8%] at end of two years. PD-L1 expression was not associated with efficacy of nivolumab and notably, no survival or response advantage was found in different levels of PD-L1 (1%, 5% and 10%) [14]. Nivolumab was found to have a better safety profile than docetaxel. Grade 3-4 toxicities were seen 7% of patients receiving nivolumab compared to 55% receiving Docetaxel. All grade toxicities were also lower with nivolumab (59% vs. 87%) [14]. Two-year overall survival rates with nivolumab versus docetaxel were 23% versus 8% in Sq NSCLC [15]. For sake of convenience and reduce hospital visits, Nivolumab 480 mg IV can be given at every 4 weeks. It is demonstrated to be equally effective [16].

Checkpoint Inhibitors as a Third Line Therapy
Nivolumab has also been evaluated as third line therapy.

b.
In another study, 35 patients having Sq NSCLC, progressing after first line and second line chemotherapy received, nivolumab as a monotherapy. Of 35 patients enrolled, nine patients (25.7%) had partial response to treatment, another 10 (28.6%) patients had stable disease. The median PFS was 4.2 months. The median OS with nivolumab treatment was 16.3 months with the OS rate at 1 year was 71.4%. The median time to response was 2.7 months (range 1.2-5.5) in the nine patients who responded to study treatment [22].

Consolidation Therapy
Durvalumab is indicated in patients not progressing on chemoradiotherapy.

First-Line Therapy
Patients with PD-L1 TPS ≥ 50%: Based on current evidence they should be treated with pembrolizumab as a monotherapy.
Patients with poor performance status and PD-L1 TPS < 50% to ≥ 1%: The may be administered pembrolizumab due to its better tolerance.

Maintenance Therapy
Pembrolizumab, if used as first line therapy should be used as maintenance therapy also.

Second-Line Therapy
With use of checkpoint inhibitors in first line therapy, their use in second line will be limited to those who have not received it as first line. Nivolumab is the only checkpoint inhibitor studied in squamous NSCLC. Pembrolizumab and atezolizumab are evaluated as a subgroup of the cohort. Atezolizumab is inferior to docetaxel in subgroup analysis and so should be avoided. Pembrolizumab needs evaluation of PD-L1 expression and benefit seems to be lower than Nivolumab (HR for OS; 0.59 vs 0.74). Nivolumab is also found useful in elderly patients.

Conclusion
For management of advanced Sq NSCLC, Pembrolizumab (monotherapy) is suggested as a first line therapy in place of chemotherapy in patients expressing PD-L1≥50%. It needs to be used with paclitaxel and carboplatin in remaining patients with PD-L1< 50%. Nivolumab is indicated as a second line therapy if checkpoint inhibitor is not used in first line therapy. Durvalumab is indicated for localised Sq NSCLC following chemoradiotherapy as consolidation therapy.