Treatment-related Toxicities in a Phase II Trial of Dasatinib in Patients with Squamous Cell Carcinoma of the Lung: A Brief Report

Abstract

Introduction

Advanced squamous cell lung cancer (SqCC) carries a poor prognosis and new therapeutic targets are needed. Several studies have examined dasatinib in NSCLC; these report significant toxicities, but also responses in patients found to harbor mutations in DDR2 or BRAF. An open-label phase II trial with dasatinib was carried out to determine the response rates in patients with SqCC who had previously failed standard chemotherapy and to correlate responses with patient genotype.

Methods

Patients were treated with dasatinib 140mg daily in 28 day cycles. Patients were included if they had stage IIIb/IV SqCC, ECOG performance status of 0 or 1, and failed standard chemotherapy.

Results

The study was halted after enrolling 5 patients, all of whom were discontinued from the trial due to excess toxicity of dasatinib administered at 140mg per day. The patients were treated for 9, 14, 24, 40, and 42 days. 3 of 5 (60%) patients experienced ≥ grade 3 toxicities (dyspnea, fatigue, AST elevation, anorexia, nausea). Intolerable grade 2 pleural effusions were noted in 2 of 5 patients. 4 of 5 patients died after 44, 52, 127, and 226 days; one patient remains alive at 279 days. No deaths were associated with the study drug.

Conclusions

Dasatinib administered at 140mg per day for the treatment of advanced SqCC of the lung is associated with excess adverse events, similar to other studies, so is not recommended in unselected patients. Further work to identify patients likely to benefit from dasatinib and in managing dasatinib-related toxicities is needed.

Introduction

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung malignancies and carries a poor prognosis. Platinum-based chemotherapy remains the standard of care; however, the discovery of oncogenic drivers and effective targeted therapeutics has resulted in significant survival improvements in certain patient subsets, notably those carrying ALK or EGFR alterations.^1,2 The majority of these oncogenic drivers are found in lung adenocarcinoma. Squamous cell carcinoma of the lung (SqCC), 25% of all NSCLC, rarely contains EGFR or ALK alterations,³ thus new therapeutic targets are needed.

Preclinical work has identified a number of somatic protein kinase mutations in SqCC,^4,5 including Discoidin Domain Receptor Tyrosine kinase 2 (DDR2) mutations, a receptor tyrosine kinase mutated in 3–4% of SqCC samples,^3,5 and rare kinase-inactivating BRAF mutations..^6,7 Dasatinib, an aminothiazole analogue and SRC family kinase (SFK) inhibitor, is active against BCR-ABL, SRC, c-KIT, and PDGFβ,⁸ and is a potent in vitro inhibitor of DDR2.⁹ Dasatinib induces cell death in DDR2-mutated cancer cell lines in vitro and decreases DDR2-mutant SqCC tumor growth in vivo in xenograft models.⁵ Dasatinib is approved for the treatment of chronic-phase or resistant chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

Recent trials evaluated dasatinib as monotherapy¹⁰ or combined with the EGFR inhibitor erlotinib^7,11 in NSCLC. One trial dosed dasatinib at 150 to 200mg alone in divided doses; common toxicities were dyspnea (grade 2, 3%; grade 3, 44%), pleural effusion (grade 2, 26%; grade 3, 18%), fatigue (grade 2, 21%; grade 3, 6%), and lymphopenia (grade 2, 15%; grade 3, 3%); mild GI intolerance was common.¹⁰ A second trial used dasatinib 50–70mg twice daily or 140mg daily, with erlotinib; toxicities included GI intolerance (71–88%), pleural effusion (35%), fatigue (74%), anemia (53%), lymphopenia (65%), and acneiform rash.⁷ A third trial dosed dasatinib at 100mg daily or 70mg twice daily, with erlotinib; complications included pleural effusion with chest tube placement in 4/21 patients, grade 3 fatigue in 4/21 patients, and moderate nausea, vomiting, and diarrhea.¹¹

Nonetheless, several responders were described.^6,7,10 Two partial responders received 70mg dasatinib twice daily and erlotinib 150mg daily: one had adenocarcinoma with an activating EGFR mutation; the other was a 59 year old female smoker with DDR2-mutated SqCC.^5,7 This second patient had tumor shrinkage, but discontinued therapy at 14 months for progressive pleural effusions. Another study reported a partial response in one patient treated with dasatinib 100mg twice daily, with remission of metastatic lung adenocarcinoma and a stable metabolically-inactive lung nodule;¹⁰ the tumor harbored a kinase-inactivating BRAF mutation.⁶

Based on these findings,^6,7,10 we carried out an open-label, phase II study of dasatinib, dosed at 140mg daily in patients with advanced stage lung SqCC. The primary outcome was to determine the overall response rate; secondary outcomes included DDR2 mutation analysis, overall and progression-free survival, and toxicities associated with dasatinib therapy.

Patients and Methods

Patient Selection

Patients were enrolled at the Dana-Farber/Harvard Cancer Center (DF/HCC) beginning in September 2011. Eligible patients were 18 years or older with measurable stage IIIb/IV lung SqCC, histologically or cytologically confirmed, who failed standard first-line platinum-based chemotherapy. Patients were excluded if pregnant, breastfeeding, known HIV positive, had uncontrolled hypertension, chronic gastrointestinal disease, heart block or significant arrhythmias, bleeding disorders or recent gastrointestinal bleeding, active infection, were incarcerated or detained, or had uncontrolled medical illness or another concurrent active malignancy. Patients could not be taking CYP3A4 inhibitors, proton pump inhibitors, H2 blockers, drugs associated with torsades de pointes, or be allergic to tyrosine kinase inhibitors. A QTc interval must have been < 470 msec. A period of at least 4 weeks must have passed since receiving chemotherapy or radiotherapy. Additional exclusion criteria included untreated or progressive brain metastases, supplemental oxygen, and symptomatic pleural or pericardial effusions unless undergoing therapeutic thoracentesis as part of non-study care.

All patients provided informed consent prior to enrollment. The study was approved by the DFCI Institutional Review Board and registered with ClinicalTrials.gov, study number NCT01491633.

Treatment Protocol

All patients were treated wtih dasatinib (Sprycel, Bristol-Myers Squibb [BMS]-354825) at a dose of 140 mg orally, daily in 28-day cycles, the maximum tolerated once daily dose reported in prior studies of dasatinib in lung cancer. In the setting of grade 3–4 adverse events, the trial drug would be held and later resumed at a lower dose of 100 mg daily. One dose de-escalation was allowed.

Study Endpoints and Design

The primary outcome was overall clinical response rate (complete response [CR] + partial response [PR]) by RECIST 1.1 criteria¹² at 8-week intervals. Secondary outcomes included outcomes among patients with DDR2 mutations; overall and progression-free survival, defined as time from study enrollment to death or disease progression, respectively; and dasatinib-associated toxicities. Patient samples were collected for molecular testing and DDR2 genotype analysis with expanded genotyping for patients with responses and no DDR2 mutations. Forty patients were planned to enroll in the trial; a two-stage Green-Dahlberg design was planned to monitor subjects for clinical response and enable early stopping for futility after 20 patients were assessed.¹³ The study had a 94.2% power to detect a ≥ 30% response rate compared to historical controls (two-sided alpha 0.041). Discontinuation criteria included patient withdrawal, progressive disease, excessive toxicity, pregnancy, and investigator decision.

Results

Six patients enrolled between November 22, 2011, and September 19, 2012. One withdrew before treatment, resulting in five evaluable patients (Table 1). All five patients stopped treatment early due to unacceptable toxicity and poor drug tolerability. All had stage IV squamous cell carcinoma; three were male. One patient had a limited smoking history (<1 cigarette/week between ages 18 and 54); otherwise all had significant smoking histories (40, 75, 100, and 120 pack-years). Patients were treated for 9, 14, 24, 40, and 42 days. Median follow-up was 127 days; 4 of 5 patients died during this period, and the survivor has been followed for 279 days. The patient who withdrew lived for 252 days. DDR2 mutations were not identified in any subject on study.

Table 1.

Baseline patient characteristics

Variable	N (%)
Age
Median (range)	59 (55–78)
Gender
Male	3 (60)
Female	2 (40)
ECOG performance status
0	2 (40)
1	3 (60)
Stage IV Disease	5 (100)
Prior Chemotherapy Regimens
Median (range)	2 (2–6)
Prior therapy
Carboplatin/Paclitaxel	4 (80)
Platinum/Gemcitabine	2 (40)
Docetaxel	2 (40)
Vinorelbine	3 (60)
Platinum/Etoposide	1 (20)
Erlotinib or Cetuximab	2 (40)
XRT	5 (100)

Treatment Course and Response

No patients were evaluable for clinical response during the trial because none were treated for 8 weeks. Three patients did not complete the first treatment cycle. Patient 1 was hospitalized for grade 3 dyspnea and stopped the study drug on day 15 of cycle 1; he withdrew from the study without receiving further treatment. Patient 2 developed a grade 2 pleural effusion requiring hospitalization on day 9 of cycle 1 and was discontinued from the study; no chest tube was required during the hospital stay. Patient 6 had a dose reduction of dasatinib to 100mg daily for fatigue on day 15; this persisted and he withdrew from the study on day 24. This patient died from his malignancy 44 days after enrollment. Of the remaining two patients, patient 4 developed fatigue during cycle 2 and discontinued the study drug on day 42; and patient 5 developed a pleural effusion and hemoptysis during cycle 2 and discontinued the study drug on day 40.

Although no patients reached the 8-week evaluation point, two patients had non-study imaging performed. Patient 1 had stable disease on a non-study assessment at day 15. Patient 5 had a non-study assessment showing disease progression on day 41, and subsequently responded to a CDK inhibitor in a phase I trial.

Toxicities

Three patients experienced ≥ grade 3 treatment-related toxicities. The most common treatment-related toxicity was pleural effusion (n=2, grade 2) (Table 2). Grade 3 toxicities included dyspnea, AST elevation, anorexia, nausea, and fatigue (1 patient each). One patient died from progressive NSCLC within 30 days from the last dose of dasatinib, not felt to be related to the study drug.

Table 2.

Toxicities encountered in trials using dasatinib for thoracic malignancies

	This Report	Haura et al	FM Johnson et al	ML Johnson et al	Miller et al	Dudek et al
Total Patients (n)	5	34	34	21	43	43
Thoracic Malignancy	Squamous Cell Lung Carcinoma	NSCLC	NSCLC	Lung Adenocarcinoma	Small Cell Carcinoma	Malignant Mesothelioma
Total Daily Dasatinib Dose	140mg	100–140mg	150–200mg	100–140mg	140mg	100–140mg
Other Agents	none	erlotinib	none	erlotinib (n=12)	none	none
Median PFS (mo)	not calculated	2.7	1.36	0.5 (dasatinib)	1.36	2.1
Pleural Effusion
grade 2	2 (40%)	6 (18%)	9 (26%)	n/a	n/a	9%
grade 3	0	0	6 (18%)	4 (19%)	5 (11%)
Dyspnea
grade 2	0	4 (12%)	1 (3%)	n/a	n/a	7.50%
grade 3	1 (20%)	1 (1%)	15 (44%)	n/a	n/a
Fatigue
grade 2	0	15 (44%)	7 (21%)	n/a	n/a	11%
grade 3	1 (20%)	0	2 (6%)	4 (19%)	6 (14%)
Anorexia
grade 2	0	11 (32%)	2 (6%)	n/a	n/a	n/a
grade 3	1 (20%)	0	0	n/a	1 (2%)	n/a
Diarrhea
grade 2	0	6 (18%)	2 (6%)	n/a	n/a	n/a
grade 3	0	2 (6%)	0	n/a	1 (2%)	n/a
Nausea
grade 2	0	8 (24%)	2 (6%)	n/a	n/a	n/a
grade 3	1 (20%)	0	0	1 (4.8%)	2 (5%)	n/a

Discussion

Advanced SqCC of the lung has a poor prognosis, and requires new therapeutic targets. Preclinical research suggests dasatinib may be effective against specific subsets of patients, particularly in patients with DDR2 mutations or inactivating BRAF mutations.^5–7,10 Three phase II trials have evaluated dasatinib dosed at 140 to 200mg daily in NSCLC, with or without erlotinib. Although toxicity was common (Table 2), several patients had responses at these doses.

Dasatinib-related toxicity and poor tolerability were the major treatment-limiting complications in our study, similar to other phase II trials, and led to early study closure. This may relate to dosing; previously, dasatinib monotherapy at 100mg twice daily had higher rates of pleural effusion (36% vs. 16%) and fatigue (41% vs. 0%) compared to 100mg/50mg dosing.¹⁰ However, dasatinib 70mg twice daily compared to dasatinib 140mg once daily, both with erlotinib, did not appear to have increased adverse events, among a small cohort.⁷ It is unknown whether erlotinib mitigates some dasatinib toxicity. Additionally, our patient population was heavily pretreated, which may have contributed to the frequent toxicities that we describe. Poor drug tolerability and limited efficacy in unselected patients is also described in other thoracic malignancies, including mesothelioma and small cell lung cancer (Table 2).^14,15 Previous trials note improved toxicity profiles among patients receiving lower initial doses,^10,11,14 suggesting that lower or twice-daily dasatinib dosing, initiating treatment at lower doses, or having a lower toxicity threshold for dose reductions, may yield more favorable drug tolerability among molecularly selected patients than seen in the current analysis.

We believe that the toxicity profile seen with dasatinib dosed at 140mg daily in NSCLC patients thus far precludes its use in unselected patients with advanced lung SqCC; however, there may be a subset of patients responsive to the drug. Unfortunately, this trial was stopped before identifying any such subgroups, though trials of dasatinib for lung cancer patients selected on the basis of DDR2 and BRAF mutations are ongoing and designed to test whether there may be benefit in individuals with these specific biomarkers (NCT01514864, NCT01744652). Future trials examining the role of dasatinib in SqCC should consider a highly selected patient cohort given the toxicities we describe.