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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two-step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m2 (i.v. days 1, 8, 15) in a 28-day cycle in the first step, and efficacy and safety in the second step. The primary end-point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment-related death occurred. While interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1-year survival rate and median progression-free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients. (Cancer Sci 2011; 102: 425–431)

Approximately 232 000 individuals are diagnosed with pancreatic cancer worldwide each year, with an annual death rate estimated at 227 000.(1) In Japan, approximately 22 000 new cases were reported in 2005.(2) Furthermore, data from 2007 show that around 24 000 individuals in Japan died from pancreatic cancer, making this tumor type the fifth leading cause of cancer-related death.(3) The majority of pancreatic cancer cases are diagnosed at an unresectable stage when prognosis is extremely poor.

Current treatment for advanced pancreatic cancer is based on systemic chemotherapy with gemcitabine. Single-agent gemcitabine has been shown to extend median overall survival (OS) to 5.65 months in chemonaïve patients compared with 4.41 months in patients who received fluorouracil.(4) Addition of other cytotoxic agents to gemcitabine has not demonstrated survival benefits over gemcitabine alone.(5–13) The potential of combining gemcitabine with biological agents in patients with advanced pancreatic cancer has also been evaluated in several phase III studies, but these trials failed to show a survival benefit.(14–19)

Epidermal growth factor receptor (EGFR)-mediated signaling is associated with various cellular processes, and the dysregulation of these processes is common in tumorigenesis.(20,21) Furthermore, EGFR is overexpressed in many tumors and its overexpression is often associated with poor prognosis.(22–26) EGFR tyrosine-kinase inhibitors (TKI, such as erlotinib) are used in the treatment of various types of solid tumors.

Erlotinib has demonstrated antitumor activity in pancreatic cell lines(27) and was subsequently assessed as a potential therapeutic agent in pancreatic cancer. In the PA.3 study (n = 569), the risk of death with erlotinib plus gemcitabine was reduced by 18% versus gemcitabine alone (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.69–0.99; P = 0.038 after adjustment for stratification factors), with a median OS of 6.24 months vs 5.91 months, respectively. Erlotinib plus gemcitabine combination therapy provided significant improvements in the 1-year survival rate (23%vs 17%; P = 0.023) and progression-free survival (PFS; HR 0.77; 95% CI, 0.64–0.92; P = 0.004).(28) As a result, this combination was approved for use in pancreatic cancer in many countries.

In Japanese patients with non-small-cell lung cancer (NSCLC), a phase II study has specifically shown that erlotinib monotherapy is well tolerated and has promising antitumor activity.(29) However, there are no data on the use of erlotinib combined with gemcitabine in Japanese patients with pancreatic cancer. This phase II study evaluated the safety and efficacy of erlotinib in combination with gemcitabine in Japanese patients with unresectable locally advanced or metastatic pancreatic cancer.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Patients.  Patients aged 20–80 years with histological/cytological evidence of unresectable locally advanced or metastatic adenocarcinoma/adenosquamous carcinoma of the pancreas were eligible for inclusion in the present study. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, adequate hematological, renal and hepatic function and a life expectancy of at least 2 months. No more than one prior regimen for pancreatic cancer was permitted. Patients who had received prior gemcitabine and/or a TKI were excluded from participation, as were those who had previously been exposed to a human epidermal growth factor receptor 2 (HER2) or EGFR inhibitor. Other key exclusion criteria were: symptomatic cerebral metastases; a concurrent lung disorder (such as idiopathic pulmonary fibrosis, interstitial lung disease [ILD] or pneumoconiosis); concurrent or previous drug-induced pneumonia; or a history of radiation to the chest.

The study complied with the Declaration of Helsinki and Good Clinical Practice guidelines. Informed consent was obtained from all patients, and the protocol was approved by ethics committees at all participating institutions.

Study design and treatment.  This was a phase II, multicentre, open-label, two-step study. In the first step, six patients were enrolled into the study and treated with oral erlotinib 100 mg/day on days 3–28, plus i.v. gemcitabine 1000 mg/m2 on days 1, 8 and 15 in a 28-day cycle. The starting doses of erlotinib and gemcitabine were chosen in reference to the PA.3 study. Dose-limiting toxicities (DLT) were assessed in these study participants using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 (NCI-CTCAE, National Cancer Institute, Bethesda, MD, USA). Dose-limiting toxicities were defined in conformity to the P1b study as follows:(30) (i) grade 4 decrease (i.e. to <500/mm3) in neutrophil count >5 days; (ii) grade ≥3 decrease (i.e. to <1000/mm3) in neutrophil count with associated fever (≥38.5°C); (iii) grade 4 decrease in platelet count (i.e. to <25 000/mm3); (iv) any grade ILD; (v) grade 4 elevation of alanine transaminase (ALT)/aspartate transaminase (AST) levels, or grade 3 elevation of ALT/AST levels >7 days; (vi) grade ≥3 non-hematological toxicity (excluding rash, hyperglycemia, γ-GTP and events that were judged to be transient/had no effect on study continuation); and (vii) dose-reduction/interruption required due to persistent adverse events (AE), which meant that the second cycle could not be started.

If treatment-related DLT occurred in no more than two of the six patients, transition to the second step of the study was permissible with approval of the Data Safety and Monitoring Committee (DSMC). If DLT occurred in three or more patients, transition to the second step was limited to those cases that were judged to be safe for this study after the DSMC had evaluated the safety data of the patients with a DLT. In the second step, it was planned that 94 patients would be treated with the same dose as the first step. Treatment was continued until disease progression, death, unacceptable toxicity or patient/investigator request.

The primary end-point of the study was safety, with secondary end-points including OS, 1-year survival rate, PFS, overall response rate (ORR), disease control rate (DCR = complete response [CR] + partial response [PR] + stable disease), pharmacokinetics (PK) and correlation of EGFR mutation status with outcomes.

Toxicity evaluation.  Adverse events were monitored and graded using NCI-CTCAE v3.0. Clinical and laboratory assessments were conducted throughout the study. Adverse events prespecified in the study to be monitored carefully were rash, diarrhea, vomiting, liver dysfunction and ILD-like events. Chest X-ray examination to assess pulmonary toxicity was conducted weekly until week 4 and every 2 weeks thereafter. In addition, chest computed tomography (CT) scan was performed every 4 weeks. The DSMC reviewed the images and clinical data associated with all potential ILD-like events. All ILD-like events were reported to be serious AE (SAE), regardless of the grade.

Efficacy evaluation.  The tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) in patients who had at least one measurable target lesion. Tumors were measured using computed tomography (CT) at baseline and on day 22 of every two cycles thereafter. Median PFS, ORR and DCR were estimated by the extramural review. The relationship between efficacy and the severity of RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) was also examined.

Pharmacokinetic evaluation.  Pharmacokinetic evaluation of erlotinib and its O-desmethylated metabolite (OSI-420) was performed in the six patients enrolled in the first step of the study. Venous blood samples were taken prior to erlotinib dosing on day 3 and day 8 of cycle 1 at 0.5, 1, 2, 4, 6, 8 and 24 h after erlotinib administration. Samples were also taken prior to gemcitabine infusion on days 1 and 8 at 0.5, 0.75, 1, 1.5, 2.5 and 4.5 h after dosing.

The plasma concentrations of erlotinib, OSI-420 and gemcitabine were measured by liquid chromatography, tandem mass spectrometry (LC-MS-MS). The LC-MS-MS analytical methods have been described previously.(31,32) Derived PK parameters included the maximum plasma drug concentration (Cmax), time to Cmax (tmax), area under the plasma drug concentration-time curve to the last plasma sample (AUClast), terminal half-life (t½) and oral clearance (Cl/F).

Biomarker analysis. EGFR mutations were assessed in patients with available tumor tissue specimens, which were formalin fixed and paraffin embedded. Samples were analyzed at a central laboratory where DNA was extracted and exons 18–21 sequenced using a nested PCR.

Statistical analysis.  Progression-free survival and OS were estimated using the Kaplan–Meier method in all patients who received at least one dose of the study treatment, with 95% CI for the median duration calculated using Greenwood’s formula. The Clopper–Pearson method was used to calculate the 95% CI around the ORR, DCR and AE rate. Multivariate analyses were performed for the occurrence of ILD-like events using the logistic regression model. Baseline characteristics investigated for this analysis included gender, age, lung metastasis, emphysema and various baseline laboratory values. The target enrollment was 100 patients, as this was required to evaluate the safety of erlotinib.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Patient characteristics.  Between December 2006 and October 2007, a total of 107 patients were enrolled (first step, n = 6; second step, n = 101) from 12 institutions (Fig. 1). One patient who enrolled into the second step did not receive treatment due to deterioration in PS prior to the start of treatment. A total of 106 patients were evaluable for safety (safety population, full analysis set).

image

Figure 1.  Kaplan–Meier estimates of (A) overall survival (OS) and (B) progression-free survival (PFS) in the study population (n = 106); (C) OS and (D) PFS according to the severity of RASH (grade ≤1 [n = 39] vs grade ≥2 [n = 67]). RASH is a composite of the terms: rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash. CI, confidence interval.

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The patient demographics and baseline characteristics are shown in Table 1. The median age was 62 years (range, 36–78) and 52.8% of patients were male. Almost all patients were chemonaïve (95.3%). The majority (75.5%) of patients had an ECOG PS of 0 and most (83.0%) had metastatic disease. Over half (63.2%) of the patients had a history of current or past smoking.

Table 1.   Baseline characteristics and demographics (n = 106)
Characteristic
  1. †Never smoker, never/hardly smoked; past smoker, passage of at least 1 month since stopping smoking (at the time of registration); current smoker, smoked within 1 month (at the time of registration). ‡Whole of pancreas (n = 1); head and body (n = 3); other (n = 1). §Tegafur, gimeracil, oteracil potassium (S-1) (n = 3); 5-fluorouracil plus leucovorin (n = 2). CA 19–9, carbohydrate antigen 19–9; CEA, carcinoembryonic antigen; ECOG, Eastern Co-Operative Group.

Median age (range) (years)62 (36–78)
Gender, n (%)
 Male56 (52.8)
 Female50 (47.2)
Median bodyweight (range) (kg)52.3 (33.1–95.0)
Smoking history,†n (%)
 Never smoker39 (36.8)
 Past smoker37 (34.9)
 Current smoker30 (28.3)
ECOG PS, n (%)
 080 (75.5)
 126 (24.5)
 20 (0)
Disease status, n (%)
 Metastatic88 (83.0)
 Locally advanced18 (17.0)
Primary tumor identified, n (%)92 (86.8)
Primary sites, n (%)
 Head46 (43.4)
 Body and tail23 (21.7)
 Body22 (20.8)
 Tail10 (9.4)
 Other5 (4.7)‡
Biliary drainage, n (%)19 (17.9)
Sites of distant metastases, n (%)
 Liver56 (52.8)
 Distant lymph nodes39 (36.8)
 Lung17 (16.0)
 Other26 (24.5)
Prior lines of therapy, n (%)
 None101 (95.3)
 One regimen5 (4.7)§
Median CA19–9 (range) (U/mL)
 Median776 (0–435 000)
Median CEA (range) (ng/mL)
 Median4.8 (0.6–1100.1)

Toxicity and dose modifications.  The median duration of erlotinib exposure was 102.5 days and its median dose intensity was 100.0 mg/day, with the majority of patients (78.3%) receiving more than 90% of the relative dose intensity. The median duration of gemcitabine treatment was 4.0 cycles and its median dose intensity was 688.0 mg/m2 per week, with approximately half of the patients (51.4%) receiving more than 90% of the relative dose intensity.

As only one patient had a DLT (grade 3 diarrhea) in the first step, the second step of the study was initiated. One hundred and six patients received at least one dose of erlotinib; these patients were assessable for toxicity. Treatment-related AE and treatment-related changes in laboratory values are summarized in Table 2; most of these were mild to moderate in severity. The most frequently reported AE was RASH, which occurred in 93.4% of the patients; most cases were mild to moderate in severity (87.7%, grade ≤2; 5.7%, grade ≥3). Other common non-hematological AE included anorexia, pruritus, fatigue, nausea and diarrhea. Most patients experienced some degree of hematological toxicity, with grade 3 or 4 neutropenia (neutrophil decreased), leucopenia (white blood cell count decreased) and anemia (hemoglobin decreased) occurring in 34.9%, 29.2% and 14.2% of patients, respectively. Only one treatment-related death occurred (due to gastrointestinal hemorrhage), which was probably due to arterial bleeding caused by the invasion of the primary tumor into the gastrointestinal tract. Although the likelihood of this event being treatment-related was deemed remote, a causal relationship could not be completely excluded because the event occurred during the study treatment administration period.

Table 2.   Treatment-related adverse events occurring in >30% of patients treated with erlotinib and gemcitabine (n = 106)
 Any grade, n (%)Grade 3, n (%)Grade 4, n (%)
  1. ALT, alanine amino transferase; AST, aspartate amino transferase.

Non-hematological
 Rash78 (73.6)3 (2.8)0 (0)
 Anorexia75 (70.8)15 (14.2)0 (0)
 Pruritus57 (53.8)1 (0.9)0 (0)
 Fatigue56 (52.8)3 (2.8)0 (0)
 Nausea56 (52.8)6 (5.7)0 (0)
 Diarrhea52 (49.1)2 (1.9)0 (0)
 Dry skin49 (46.2)0 (0)0 (0)
 Stomatitis38 (35.8)0 (0)0 (0)
 Pyrexia32 (30.2)0 (0)0 (0)
Hematological
 White blood cell count decreased85 (80.2)31 (29.2)0 (0)
 Platelet count decreased77 (72.6)9 (8.5)0 (0)
 Hemoglobin decreased76 (71.7)13 (12.3)2 (1.9)
 Hematocrit decreased73 (68.9)8 (7.5)0 (0)
 Neutrophil decreased73 (68.9)32 (30.2)5 (4.7)
 Red blood cell count decreased72 (67.9)8 (7.5)0 (0)
 ALT increased59 (55.7)10 (9.4)0 (0)
 AST increased57 (53.8)4 (3.8)1 (0.9)
 Weight decreased53 (50.0)3 (2.8)0 (0)
 Lymphocyte count decreased46 (43.4)14 (13.2)0 (0)
 Blood albumin decreased35 (33.0)0 (0)0 (0)
 Gamma-glutamyltransferase increased35 (33.0)12 (11.3)1 (0.9)

Treatment-related SAE were reported in 26 (24.5%) patients. These included nine ILD-like events (8.5%), the majority of which (n = 7) were grade 1–2 in severity. Importantly, all of these nine patients recovered or improved, and four of these patients did so without any treatment for ILD-like events. Other treatment-related SAE were anorexia (3.8%), vomiting, pyrexia and abnormal hepatic function (1.9% each). The baseline characteristics, treatment and outcomes of patients who developed treatment-related ILD-like events during the study are detailed in Table 3. The onset times of ILD-like events ranged from 7 to 187 days after the start of treatment. In these patients, a relatively long survival was observed (from 119 to 568+ days), and five patients received post-study therapy. All of these nine patients were past or current smokers, and six had emphysema at baseline (not detected prior to treatment, but diagnosed at the extramural review by a radiologist in the DSMC). Multivariate analyses were performed for the occurrence of ILD-like events using the logistic regression model and emphysema at baseline was indicated as a risk factor for onset of ILD-like events (odds ratio [95% CI], 12.13 [1.01–145.7]; P = 0.0491).

Table 3.   Characteristics, treatment and outcomes of patients with treatment-related ILD-like events (n = 9)
EventGenderAge (years)Smoking status†Days on treatmentILD maximum gradeSuspicious findings of ILDSteroidsOxygenILD outcomePresence of emphysema (assessed by radiologist)Survival outcome (days)Post-therapy (chemotherapy)
  1. †Past smoker, passage of at least 1 month since stopping smoking (at the time of registration); current smoker, smoked within 1 month (at the time of registration). CT, computed tomography; F, female; ILD, interstitial lung disease; M, male.

Lymphoid ILDM62Past821PyrexiaNoneNoImprovedYes362Yes
ILDM42Current503PyrexiaPulseYesRecoveredYes517Yes
Organising pneumoniaM60Past1832Respiratory symptomsNoneNoImprovedYes568+Yes
ILDF62Past1132CoughOralNoRecoveredYes376No
ILDF74Past1113Cough, dyspneaPulseYesImprovedNone183No
ILDM60Current251PyrexiaPulseNoRecoveredNone119Yes
ILDM77Past71X-rayNoneNoRecoveredYes255No
ILDM55Past1871CTNoneNoRecoveredYes415No
ILDF60Current762CoughOralNoRecoveredNone346Yes

Adverse events led to erlotinib discontinuation in 30 patients (28.3%) and gemcitabine discontinuation in 27 patients (25.5%). The main reasons for treatment discontinuation were ILD (n = 6) and anorexia (n = 3); no patient discontinued treatment due to RASH or diarrhea. Due to the onset of AE, a total of 65 patients (61.3%) required one or more interruptions of erlotinib (36 patients [34.0%] for longer than seven consecutive days and 17 patients [16.0%] for longer than 14 consecutive days) and 56 patients (52.8%) had one or more skip of gemcitabine. Modifications in the erlotinib or gemcitabine dosage were required in 17 (16.0%) and 11 (10.4%) patients, respectively, due to AE.

Efficacy.  The median OS was 9.23 months (95% CI, 8.31–10.78; Fig. 1A) and the 1-year survival rate was 33% (95% CI, 24–42). Median PFS was 3.48 months (95% CI, 2.63–3.78; Fig. 1B). Among the patients evaluable for tumor response (n = 64), the ORR was 20.3% (13/64; 95% CI, 11.3–32.2) and the DCR was 50.0% (95% CI, 37.2–62.8; CR, n = 0; PR, n = 13; stable disease, n = 19).

The median OS was longer in patients who experienced RASH of grade ≥2 (n = 67) than in those with RASH of grade ≤1 (n = 39) (10.25 months [95% CI, 8.80–12.12] vs 8.31 months [95% CI, 6.18–9.99], respectively; Fig. 1C) and the 1-year survival rate was higher (39% [95% CI, 27–50] vs 23% [95% CI, 10–36], respectively). Similarly, the median PFS was longer in patients with RASH of grade ≥2 versus those with RASH grade ≤1 (3.61 months [95% CI, 3.48–5.32] vs 1.81 months [95% CI, 1.64–3.48]; Fig. 1D). While there was no notable difference in ORR between patients with RASH grade ≥2 and those with grade ≤1 (21.1% [95% CI, 9.6–37.3] vs 19.2% [95% CI, 6.6–39.4]), the DCR was higher in those with more severe RASH (60.5% [95% CI, 43.4–76.0] vs 34.6% [95% CI, 17.2–55.7]).

Pharmacokinetics.  Plasma sampling for PK analyses was performed in all six patients enrolled in the first step. On day 8, the values of Cmax were 1760 ± 456.9 ng/mL (mean ± SD) for erlotinib, 169.7 ± 64.5 ng/mL for OSI-420 and 22 700 ± 3272.9 ng/mL for gemcitabine. The AUClast was 29 001 ± 6560 h ng/mL, 2748 ± 788 h ng/mL and 10 717 ± 1458 h ng/mL (mean ± SD), respectively. The mean tmax was 8.0 h (range, 2.0–23.9 h), 9.0 h (2.0–23.9 h) and 0.51 h (0.45–0.57 h), respectively. Also on day 8, the mean plasma t1/2 was 54.92 h (range, 9.25–144.61 h), 32.79 h (10.36–60.46 h), and 0.63 h (0.31–1.14 h), respectively. The Cl/F of erlotinib and gemcitabine showed interindividual variability; the Cl/F on day 8 was 3972.6 ± 772.1 mL/h (mean ± SD; coefficient of variation 19.4%) and 146 580.4 ± 31 101.3 mL/h (21.2%), respectively.

Biomarker analysis.  Of the 106 patients enrolled, EGFR mutation status was evaluated in 47 patients (44.3%), all of whom had wild-type EGFR. The mutation status of the remaining patients was classified as unknown because samples were not available (30.2%), not examined (9.4%) or the results following sequencing were inconclusive (16.0%).

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

This study was designed to initially assess the safety of erlotinib with gemcitabine for Japanese patients with pancreatic cancer, in whom there had been no prior exposure to either drug. As no significant safety concerns were raised in the first step of the study, enrollment of a further 101 patients was performed. Although the incidence of AE in this study was higher than in the PA.3 study, the incidence of grade 3–4 AE was similar.(28) Despite these results, no new AE specific to Japanese patients were observed. As expected, RASH and gastrointestinal events were among the most common AE in this study, and most of these cases were mild to moderate in severity.

Interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%) in the current study, while its incidence was reported to be 2.4% in patients treated in the erlotinib plus gemcitabine arm of the PA.3 study.(28) In addition, in Japanese patients with advanced pancreatic cancer, ILD-like events were reported in two (6.1%) of 33 patients treated with gemcitabine plus S-1, and were reported in three (1.1%) of 264 patients with gemcitabine monotherapy, respectively.(33,34) Likewise, the higher incidence of ILD-like events were documented using S-1 or erlotinib in combination with gemcitabine compared with gemcitabine as monotherapy in patients with pancreatic and biliary tract cancer.(35) On another front, outside of Japan, a high incidence of ILD-like events was reported in gemcitabine and paclitaxel combination therapy in patients with NSCLC.(36) From the above information, considering the higher incidence of ILD when gemcitabine is used in combination, an additive effect from such combinations cannot be ruled out.

In NSCLC, Japanese patients have an increased risk of developing ILD-like events when treated with EGFR TKI.(29,37–39) Fatal cases of ILD-like events have been reported following EGFR TKI administration for the treatment of NSCLC.(37–41) Importantly, however, no patients died due to an ILD-like event in this study. Seven patients experienced ILD-like events of grade 1–2 in severity. This may be due to active management of ILD-like cases during the study period. This management included regular and immediate chest X-rays, in addition to diagnosis with CT scans after any early signs and symptoms were observed (e.g. pyrexia, cough or dyspnea), timely discontinuation of the antitumor drugs (as a precautionary measure in case these drugs were associated with the symptoms) and appropriate treatment for the events (including oral/pulse steroids). By appropriately treating the early symptoms of ILD-like events, patients could restart antitumor therapy (chemotherapy: treatment change). In this study, the onset time for ILD-like events varied markedly between patients (7–187 days). It is therefore necessary to monitor the patients throughout the treatment period.

All of the patients who developed ILD in this study were current or past smokers, and smoking status has been shown to be a risk factor for ILD in the NSCLC population.(38) Results from the multivariate analyses in this study suggest that emphysema is also a risk factor for developing ILD; six of the nine patients with ILD-like events were diagnosed with emphysema at baseline. Although the number of reports of an ILD-like event may have been artificially elevated due to underlying patient baseline characteristics and the active management of ILD-like events, these results demonstrate the need to consider the risk of ILD-like events in Japanese patients treated with TKI. In particular, it is important that chest CT scans are closely checked for the presence of emphysema or comorbid ILD and that pulmonary status is assessed prior to treatment administration.

This study corroborates the results of the combination of gemcitabine and erlotinib shown in the PA.3 study. The median OS in this study of 9.23 months was longer than those reported in trials with gemcitabine alone. In this study, patients who experienced skin toxicity of grade ≥2 had better outcomes than those with less severe toxicity or the overall study population. Retrospective analyses of data from the PA.3 and AViTA studies have found a significant association between the development of skin toxicity and efficacy in patients with pancreatic cancer treated with erlotinib-based therapy, although the precise mechanisms for the association between skin toxicity and effectiveness are unknown.(28,41,42)

Although the presence of mutations in the tyrosine-kinase region of the EGFR gene appears to predict a better response to erlotinib in NSCLC,(43,44) this has not yet been evaluated in pancreatic cancer. EGFR mutations are very rare in patients with pancreatic cancer;(45–47) indeed in the present study, no EGFR mutations were detected. Further work is required to determine whether EGFR mutations can be used as predictive markers for improved survival in Japanese patients receiving erlotinib and gemcitabine as treatment for advanced pancreatic cancer.

In conclusion, the present study shows that erlotinib in combination with gemcitabine is generally well tolerated in Japanese patients with advanced pancreatic cancer. This combination is associated with efficacy and survival outcomes, and the results of this study are consistent with the findings of the global PA.3 study.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

The authors would like to thank all the patients, investigators and site staff involved in the study. We are grateful to Masahiro Fukuoka for acting as a medical advisor for this study. The authors also thank Abdul Al Khateeb of Gardiner–Caldwell Communications for editorial assistance. This study was sponsored by Chugai Pharmaceutical Co., Ltd. Editorial assistance from Abdul Al Khateeb of Gardiner–Caldwell Communications was funded by Chugai Pharmaceutical Co., Ltd.

Disclosure Statement

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References

Junji Furuse received honoraria for lecture fees from Bayer, Eli Lilly Japan, Taiho Pharmaceutical and Eisai; Kazuhiko Nakagawa received honoraria for lecture fees from Eli Lilly Japan, Chugai Pharmaceutical and AstraZeneca; Takuji Okusaka, Akihiro Funakoshi, Tatsuya Ioka, Kenji Yamao, Shinichi Ohkawa, Narikazu Boku, Yoshito Komatsu, Shoji Nakamori, Haruo Iguchi, Tetsuhide Ito and Kohei Nakachi have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure Statement
  8. References
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