Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib

Figures & data

Table 1 Summary of Key Clinical Data from Studies of Regimens Approved and Recommended in Key Guidelines for the Treatment of Advanced Squamous Cell Lung Cancer

Study	Number of NSCLC Patients in Trial/Number with Lung SCC	Patient Population	Median PFS	Median OS	Survival HR vs Chemotherapy in Lung SCC Patients (95% CI)
First-line treatment
Pembrolizumab vs platinum-based chemotherapy (KEYNOTE-024)^Citation92,Citation93	305/56	PD-L1 TPS ≥50%	10.3 vs 6.0 months; P<0.001	30.0 vs 14.2 months; P=NR	PFS 0.35 (0.17–0.71)
Pembrolizumab vs platinum-based chemotherapy (KEYNOTE-042)^Citation11	1274/492	PD-L1 TPS ≥1%	TPS ≥1%: 5.4 vs 6.5 months; P=NR TPS 1–49%: NR	TPS ≥1%: 16.7 vs 12.1 months; HR=0.81; P=0.0018 TPS 1–49%: 13.4 vs 12.1 months; HR=0.92	NR (SCC patients were not analyzed separately)
Pembrolizumab + platinum-based chemotherapy vs platinum-based chemotherapy (KEYNOTE-407)^Citation94	559/559	Unselected (PD-L1 TPS <1% and ≥1%)	6.4 vs 4.8 months; P<0.001	15.9 vs 11.3 months; HR=0.64; P<0.001	PFS 0.56 (0.45–0.70)
Nivolumab + ipilimumab vs platinum-based chemotherapy (CheckMate 227)^Citation13,Citation15	PD-L1 ≥1%: 1189/350	Unselected (PD-L1 <1% and ≥1%)	PD-L1 ≥1%: 5.1 vs 5.6 months; HR 0.82	PD-L1 ≥1%: 17.1 vs 14.9 months; P=0.007	PD-L1 ≥1%: OS 0.69 (0.52–0.92)
Atezolizumab vs platinum-based chemotherapy (IMpower110)^Citation16	554/167	PD-L1 ≥1% on TC or IC	TC3 or IC3 WT: 8.1 vs 5.0 months; P=0.0070	TC3 or IC3 WT: 20.2 vs 13.1 months; HR=0.59; P=0.0106	OS 0.56 (0.23–1.37) (for TC3 or IC3 WT)
Second-line treatment
Nivolumab vs docetaxel (CHECKMATE 017)^Citation23	272/272	Unselected patients with progressive disease after first-line platinum-based chemotherapy	3.5 vs 2.8 months; P<0.001	9.2 vs 6.0 months; P<0.001	PFS 0.62 (0.47–0.81)
Ramucirumab + docetaxel vs docetaxel (REVEL)^Citation22	1253/328	Unselected patients with progressive disease after first-line platinum-based chemotherapy	Overall population: 4.5 vs 3.0 months; P<0.0001	Patients with SCC: 9.5 vs 8.2 months; HR=0.88	NR (SCC patients not analyzed separately)
Atezolizumab vs docetaxel (OAK)^Citation24	850/222	Unselected patients with progressive disease after ≤2 previous chemotherapy regimens	Overall population: 2.8 vs 4.0 months; P=NS	Overall population: 13.8 vs 9.6 months; HR=0.73; P=0.0003	OS 0.73 (0.54–0.98)
Pembrolizumab 2 mg/kg vs pembrolizumab 10 mg/kg vs docetaxel (KEYNOTE-010)^Citation84	1033/222	Patients with PD-L1 TPS ≥1% and progressive disease after platinum-based chemotherapy	Overall population: 3.9 vs 4.0 vs 4.0 months; P=NS	Overall population: 10.4 vs 12.7 vs 8.5 months; P<0.001 for both pembrolizumab groups vs docetaxel	OS 0.74 (0.50–1.09); P=NS

Abbreviations: CI, confidence intervals; HR, hazard ratio; IC, tumor-infiltrating immune cells; NR, not reported; NS, not significant; NSCLC, non-small-cell lung carcinoma; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; SCC, squamous cell carcinoma; TC, tumor cells; TPS, tumor proportion score; WT, wild-type.

Table 2 Summary of Key Clinical Studies of Therapy Targeting EGFR in Patients with Advanced Squamous Cell Lung Carcinoma, Including the Investigation of Biomarkers Predicting Response to Therapy

Study	Number of NSCLC Patients in Trial/Number with Lung SCC	Patient Population	Median PFS	Median OS	Survival HR vs Chemotherapy in SCC Patients (95% CI)	Predictive Biomarkers
Necitumumab + gemcitabine-cisplatin vs gemcitabine-cisplatin (SQUIRE)^Citation33,Citation39	1093/1088	Unselected patients with lung SCC	5.7 vs 5.5 months; P=0.02	11.5 vs 9.9 months; P=0.01	PFS 0.85 (0.74–0.98) OS (overall population) 0.84 (0.74–0.96)	Median^Citation37 OS significantly increased (>3.9 months) in necitumumab-treated patients with tumors expressing any level of the EGFR protein compared with patients not expressing EGFR
Cetuximab + cisplatin and vinorelbine vs cisplatin and vinorelbine (FLEX)^Citation34	1125/377	Chemotherapy-naïve patients with NSCLC and IHC evidence of EGFR expression in at least one positively stained tumor cell	4.8 vs 4.8 months; P=NS	11.3 vs 10.1 months; P=0.04	OS 0.80 (0.64–1.0)	NR
Cetuximab plus carboplatin-paclitaxel ± bevacizumab vs carboplatin-paclitaxel ± bevacizumab (SWOG S0819)^Citation38	1313/321	Newly diagnosed or recurrent NSCLC	Overall population: 4.6 vs 4.5 months; P=0.83	Overall population: 10.9 vs 9.2 months; P=0.22	PFS 0.88 (0.70–1.11); P=0.29 OS 0.85 (0.67–1.07); P=0.17	EGFR-FISH positivity was associated with significantly improved OS (11.8 vs 6.1 months; HR=0.58 [95% CI=0.39–0.86]; P=0.01) with cetuximab treatment vs chemotherapy
Erlotinib vs placebo (BR21)^Citation45	587/222	Disease progression after first- or second-line chemotherapy	SCC patients: 2.3 vs 1.8 months; P=NR	5.6 vs 3.6 months; P=NR	PFS 0.48 (0.35–0.67) OS 0.60 (0.44–0.82)	NR
Erlotinib vs docetaxel (TAILOR)^Citation46	219/54	Wild-type EGFR and recurrence/progression after platinum-based chemotherapy	Overall population: 2.4 vs 2.9 months; P=0.02	Overall population: 5.4 vs 8.2 months; P=0.05	PFS 0.57 (0.32–1.03) OS 0.90 (0.49–1.65)	KRAS mutation was not associated with prognosis
Erlotinib vs pemetrexed or docetaxel (PROSE)^Citation47	263/47	Advanced NSCLC and progression during or within 6 months after first-line platinum-based chemotherapy	NR	7.7 vs 9.0 months; P=0.15	PFS NR OS 1.08 (0.75–1.57)	Patients classified as VS-P had shorter OS on erlotinib than chemotherapy (HR 1.72 [95% CI 1.08–2.74]; P=0.022). No difference in OS between treatments among VS-G patients
Afatinib vs erlotinib (LUX-Lung 8)^Citation32,Citation48,Citation58	795/795*	Lung SCC and progression after platinum-based chemotherapy	2.6 vs 1.9 months; P=0.01	7.9 vs 6.8 months; P=0.008	PFS 0.81 (0.69–0.96) OS 0.81 (0.69–0.95)	In afatinib- but not erlotinib-treated patients, median PFS and OS were longer in those with ErbB mutations vs those without; HER2 mutation may predict better outcomes with afatinib vs erlotinib; EGFR overexpression did not predict PFS or OS benefit with afatinib vs erlotinib
Cetuximab vs cetuximab plus taxane/carboplatin (BMS 099)^Citation35	676/132	Chemotherapy-naïve patients with advanced NSCLC	4.40 vs 4.24 months; P=0.236	9.69 vs 8.38 months; P=0.169	PFS 0.70 (0.47–1.05)^† OS 0.873 (0.599–1.275)	NR

Notes: *32 patients had mixed histology; ^†Subset variable not prespecified in the statistical analysis plan.

Abbreviations: BMS, Bristol-Myers Squibb; CI, confidence interval; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemical; ITT, intent to treat; NR, not reported; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; SCC, squamous cell carcinoma; VS-G, Veristrat^®-good; VS-P, Veristrat^®-poor.

Figure 1 The ErbB family of receptor tyrosine kinases and the mechanism of action of targeted therapy. Data from these studies.^33,95,96

Abbreviations: EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2.

Figure 2 Progression-free (A) and overall (B) survival in the overall study population of LUX-Lung 8. – Reprinted from The Lancet Oncology, Vol 16, Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial, pp. 897–907, Copyright (2015), with permission from Elsevier.⁵⁸

Abbreviations: CI, confidence interval; HR, hazard ratio.

Table 3 Most Common Treatment-Related Adverse Events Seen in LUX-Lung 8*.

	Afatinib (n=392)				Erlotinib (n=395)
	Grade 1	Grade 2	Grade 3	Grade 4	Grade 1	Grade 2	Grade 3	Grade 4
Diarrhea	165 (42%)	68 (17%)	39 (10%)	2 (<1%)	94 (24%)	28 (7%)	9 (2%)	1 (<1%)
Rash or acne^†	157 (40%)	83 (21%)	23 (6%)	0 (0%)	142 (36%)	83 (21%)	41 (10%)	0 (0%)
Stomatitis^†	65 (17%)	32 (8%)	16 (4%)	0 (0%)	21 (5%)	13 (3%)	0 (0%)	0 (0%)
Fatigue^†	33 (8%)	20 (5%)	6 (2%)	0 (0%)	24 (6%)	17 (4%)	7 (2%)	0 (0%)
Nausea	35 (9%)	13 (3%)	4 (1%)	0 (0%)	20 (5%)	5 (1%)	3 (<1%)	0 (0%)
Decreased appetite	31 (8%)	16 (4%)	3 (<1%)	0 (0%)	24 (6%)	15 (4%)	2 (<1%)	0 (0%)
Paronychia^†	28 (7%)	11 (3%)	2 (<1%)	0 (0%)	9 (2%)	7 (2%)	1 (<1%)	0 (0%)
Dry skin	28 (7%)	4 (1%)	2 (<1%)	0 (0%)	34 (9%)	7 (2%)	0 (0%)	0 (0%)
Pruritus	22 (6%)	9 (2%)	1 (<1%)	0 (0%)	37 (9%)	10 (3%)	0 (0%)	0 (0%)
Vomiting	20 (5%)	8 (2%)	3 (<1%)	0 (0%)	7 (2%)	4 (1%)	2 (<1%)	0 (0%)
Dehydration	2 (<1%)	5 (1%)	3 (<1%)	4 (1%)	0 (0%)	0 (0%)	3 (<1%)	0 (0%)

Notes: *Includes grade 1–2 adverse events that occurred in >10% of patients, or grade 3–5 adverse events that occurred in >1% patients within any treatment group. ^†Grouped term. Reprinted from The Lancet Oncology, Vol 16, Soria JC, Felip E, Cobo M, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial, pp. 897–907, Copyright (2015), with permission from Elsevier.⁵⁸

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