Med Oncol (2015) 32:134 DOI 10.1007/s12032-015-0587-x
ORIGINAL PAPER
Switch maintenance treatment with oral vinorelbine and bevacizumab after induction chemotherapy with cisplatin, gemcitabine and bevacizumab in patients with advanced nonsquamous non-small cell lung cancer: a phase II study Roberto Petrioli1 • Edoardo Francini2 • Anna Ida Fiaschi3 • Letizia Laera1 Luca Luzzi4 • Piero Paladini4 • Claudia Ghiribelli4 • Luca Voltolini5 • Vincenzo Bianco2 • Giandomenico Roviello1
•
Received: 3 March 2015 / Accepted: 14 March 2015 / Published online: 22 March 2015 Ó Springer Science+Business Media New York 2015
Abstract The present study evaluated the efficacy and safety of cisplatin (Cis), gemcitabine (Gem) and bevacizumab (Bev), followed by maintenance treatment with Bev and oral vinorelbine (Vnb), in patients with advanced non-squamous non-small cell lung cancer (NSCLC). The patients were administered six cycles of induction chemotherapy consisting of intravenously (i.v.) Cis 70 mg/m2 on day 1 plus i.v. Gem 1000 mg/m2 on days 1 and 8, plus i.v. Bev 7.5 mg/kg on day 1, every 3 weeks. Patients who did not experience tumor progression remained on maintenance treatment with Bev combined with oral Vnb 60 mg/m2 weekly until occurrence of disease progression or unacceptable toxicity. Thirty-seven patients were enrolled: The median age was 67 years (range 38–81); 22 patients were male, and 30 patients had stage IV tumors. The response rate was 32.4 % (95 % CI 18–49.7). The 9-month disease-control rate was 45.9 %. The median PFS was 8.4 months (95 % CI 4.4–10.7), and the median OS was 18.1 months (95 % CI 15.3–20.8 months). Grade 3–4 neutropenia occurred in 6 (16.2 %) patients and grade 3–4
& Roberto Petrioli [email protected] 1
Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Bracci, 53100 Siena, Italy
2
Medical Oncology Unit, Policlinico Umberto I Hospital, University of Rome, Rome, Italy
3
Pharmacology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
4
Unit of Thoracic Surgery, Surgery Department, University of Siena, Siena, Italy
5
Unit of Thoracic Surgery, Policlinico Careggi, University of Firenze, Florence, Italy
thrombocytopenia in four (10.8 %) patients during induction chemotherapy. Bev- or Vnb-associated toxicities were mild. Switch maintenance treatment with Bev and oral Vnb after first-line Cis, Gem and Bev is feasible in patients with non-squamous NSCLC and may achieve encouraging results in terms of PFS and OS. Keywords Bevacizumab Cisplatin Gemcitabine Maintenance Lung cancer Vinorelbine
Introduction Non-small cell lung cancer (NSCLC) is the most common malignancy and the leading cause of cancer death worldwide. Although surgical resection offers the only chance of long-term cure, the majority of NSCLC patients present with locally advanced or metastatic disease at diagnosis, and prognosis is very poor [1, 2]. Wild-type EGFR and ALK non-rearranged patients have to be treated with combination chemotherapy which usually includes cisplatin (Cis) or carboplatin, gemcitabine (Gem), taxanes, vinorelbine (Vnb), pemetrexed and antiangiogenic agents such as bevacizumab (Bev). Bev is a recombinant, humanised, monoclonal antibody against the vascular endothelial growth factor (VEGF) approved for the first-line treatment of advanced NSCLC [3–6]. The open-label Eastern Cooperative Oncology Group (ECOG) 4599 study showed that the addition of Bev to carboplatin–paclitaxel significantly extended overall survival (OS) and progression-free survival (PFS) and improved the objective response rate (RR) versus chemotherapy alone [5]. The double-blind AVAiL trial showed that Bev combined with Cis plus Gem improved the RR and significantly extended the PFS versus placebo, but the OS was not significantly
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different between the two treatment groups [6, 7]. In both trials, all of the patients were offered maintenance Bev until disease progression or unacceptable toxicity after six cycles of induction chemotherapy. The main rationale for using the antiangiogenic agent Bev as maintenance treatment is that tumor angiogenesis is critical for tumor progression. VEGF promotes angiogenesis, and overexpression of the VEGF has been correlated with poor prognosis in various malignancies, including NSCLC [8– 10]. However, despite the encouraging results obtained with combination chemotherapy followed by single-agent Bev as maintenance, prognosis of patients with advanced NSCLC remains poor, with PFS usually \6–7 months and median OS \15 months [6, 7]. In the search of improving the outcome of patients with advanced NSCLC, switch maintenance therapy is another possible option which provides a different agent that was not included as part of the first-line regimen. In this setting, Vnb is a chemotherapy agent which has showed activity and tolerability in lung cancer, and its oral formulation achieved promising results and good safety profile also in elderly patients [11–16]. The activity and tolerability of oral Vnb in patients with NSCLC was the main rationale for why this agent was chosen as maintenance chemotherapy in the current study. The aim of this a phase II study was to evaluate the activity and tolerability of a switch maintenance treatment consisting of Bev and oral Vnb in advanced non-squamous NSCLC patients after induction chemotherapy with Cis, Gem and Bev.
Patients and methods Eligibility criteria The study enrolled patients with histologically proven, measurable, stage IIIB or IV non-squamous NSCLC. No prior chemotherapy for advanced disease was allowed. The other eligibility criteria included age more than 18 years, ECOG performance status (PS) of 0–2, bidimensionally measurable disease, a life expectancy of at least 3 months, adequate hematological parameters (an absolute neutrophil count of C1.5 9 109/l and a platelet count of C100 9 109/ l), creatinine\1.5 times the upper limit of the normal range and total bilirubin levels \3 9 the upper normal limit, aspartate and alanine aminotransferase \3.0 9 the upper normal limit and the absence of a second primary tumor other than non-melanoma skin cancer or in situ cervical carcinoma. Exclusion criteria were histological evidence of predominant squamous cell cancer; a history of gross hemoptysis (C2.5 ml); brain metastases or prior treatment for brain metastasis; uncontrolled pleural or pericardial
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effusion or ascites; pregnancy or lactation; a history of documented hemorrhagic diathesis or coagulopathy; therapeutic anticoagulation; regular use of aspirin ([325 mg per day), non-steroidal antiinflammatory agents known to inhibit platelet function; radiation therapy within 21 days before enrollment or major surgery within 28 days before enrollment; clinically significant cardiovascular disease; and medically uncontrolled hypertension. This study was approved by the local ethical and scientific committee, and all of the patients gave their written informed consent. Patient evaluation Patients were seen at the start of every chemotherapy cycle for a physical examination, monitoring of symptoms and toxic effects, assessment of renal function and a complete blood count. After baseline evaluation, disease was reassessed every three cycles (approximately every 9 weeks) during induction chemotherapy. If patients withdrew from treatment for other reasons than progressive disease, follow-up tumor assessments were repeated every 2 months until disease progression. Objective tumor response was evaluated according to RECIST criteria. After completion of the induction chemotherapy, patients continued to have CT scans every 2 months for 6 months and thereafter at a 3-month interval until there was evidence of disease progression. Treatment delivery Patients received a maximum of six cycles of induction chemotherapy consisting of intravenously (i.v.) Cis 70 mg/ m2 on day 1 plus i.v. Gem 1000 mg/m2 on days 1 and 8, plus i.v. Bev at a dose of 7.5 mg/kg on day 1, every 3 weeks. Maintenance treatment consisted of Bev at a dose of 7.5 mg per kilogram on day 1 every 3 weeks and weekly oral Vnb 60 mg/m2. Toxicity Toxicity was assessed using the common toxicity criteria of the National Cancer Institute (NCI), version 2.0. Treatment was delayed if, on the planned day of treatment, the neutrophil count was \1500/mm3, the platelet count was\100,000/mm3 or the patient had persistent diarrhea or stomatitis [grade 1. Any patient who required more than 2 weeks for recovery from adverse reactions was excluded from the study. In the event of grade 4 hematological or any other severe (Cgrade 3) organ toxicity in individual patients, chemotherapeutic drug doses were reduced by 25 % for subsequent courses.
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Statistical considerations The primary end point was 9-month disease-control rate (DCR). A previous trial investigating Cis, Gem and Bev followed by Bev maintenance indicated that about 60 and 30 % of patients were progression-free 6 and 9 months after the start of treatment, respectively [6]. The hypothesis for the current study was that, using the combined Bev and oral Vnb as maintenance therapy, at least 50 % of patients would be progression-free 9 months after the start of chemotherapy. It was calculated that 39 patients would have to be recruited to yield a 80 % probability to correctly select the treatment when it is superior by absolute difference of 20 % in 9-month DCR [17]. PFS was calculated as the time from the first chemotherapy infusion to disease progression or death. Other secondary end points include safety, OS (measured from the date of the start of treatment to the date of death) and RR. Kaplan–Meier method was used to determine PFS and OS. Statistical analyses were conducted by STATAiC software.
Page 3 of 7 134 Table 1 Patient characteristics Characteristic
No. of patients (n = 37)
Age, years Median
67
Range
(38–81)
Sex Male
22
Female
15
ECOG PS 0
10
1
19
2
8
Disease stage IIIB IV
7 30
Surgery Yes
4
No
33
Radiotherapy Yes
4
No
33
Results Patient characteristics Between March 2011 and May 2014, 37 newly diagnosed patients with advanced non-squamous NSCLC were enrolled in the study. Baseline characteristics of the patients are presented in Table 1. In all, eight (21.6 %) patients had a PS of 2 and 30 (81.1 %) had stage IV. Four patients (10.8 %) had prior resection of their primary tumor with curative intent and were offered our treatment protocol after documentation of unresectable progressive or metastatic disease. All patients had not received any form of anticancer therapy for advanced disease; four patients had been previously treated with radiotherapy which had been stopped at least 6 months before entering in the study. Efficacy All of the 37 enrolled patients received three Cis/Gem/Bev treatment cycles (range 3–6 cycles) and were evaluable for response and toxicity. One patients (2.7 %) achieved complete remission and 11 (29.7 %) achieved partial remission, making the RR 32.4 % (95 % CI 18–49.7). Fourteen patients (37.8 %) achieved stable disease as their best response to therapy, and DCR was 70.2 % (95 % CI 53–84.1) (Table 2). Median duration of response to prior induction chemotherapy was 6.5 months (95 % CI 4.8–7.5).
Table 2 Best response to treatment Response
Cis/Gem/Bev ? Vnb/Bev
CR
1 (2.7 %)
PR
11 (29.7 %)
SD
14 (37.8 %)
PD
8 (21.6 %)
PR ? SD
12 (32.4 %)
9-month DCR
17 (45.9 %)
(95 % CI 16.7–56.6) (95 % CI 26.7–73.5) CR complete remission, PR partial remission, SD stable disease, PD progressive disease, DCR disease-control rate, Cis cisplatin, Gem gemcitabine, Bev bevacizumab, Vnb vinorelbine, CI confidence interval
The 26 patients who achieved DCR after induction chemotherapy with Cis/Gem/Bev received maintenance chemotherapy with oral Vnb and Bev for a median of 6 months (range 1–26 months). Twenty-two patients discontinued maintenance chemotherapy because of disease progression; one patient was lost to follow-up after 4 months from the onset of maintenance treatment; and three patients are still on maintenance treatment at the time of this writing. The 9-month DCR was 45.9 % (95 % CI 26.7–73.5). The median PFS time was 8.4 months (95 % CI 4.4–10.7).
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Eleven patients (29.7 %) received a second-line chemotherapy with pemetrexed, four patients were treated with docetaxel (10.8 %), and three patients (8.1 %) received a third-line chemotherapy with erlotinib. At a median follow-up of 19.2 months (range 5.5–26.4), a total of 30 patients were deceased: The median OS time was 18.1 months (95 % CI 15.3–20.8 months) (Fig. 1).
Med Oncol (2015) 32:134 Table 3 Summary of adverse events during induction chemotherapy Grade 2
Grade 3
Grade 4
Hematological Neutropenia
18 (48.6 %)
4 (10.8 %)
2 (5.4 %)
Anemia
23 (62.1 %)
1 (2.7 %)
0
Thrombocytopenia
24 (64.8 %)
2 (5.4 %)
2 (5.4 %)
Nausea
20 (54 %)
2 (5.4 %)
0
Vomiting
9 (24.3 %)
0
0
Fatigue
17 (45.9 %)
2 (5.4 %)
0
Stomatitis
6 (16.2 %)
0
0
Non-hematological
Treatment toxicity The incidence of toxicity during induction chemotherapy is summarized in Table 3. Grade 3–4 neutropenia occurred in six patients (16.2 %), grade 3–4 thrombocytopenia in four patients (10.8 %), and grade 3 anemia in one patient (2.7 %). Grade 3 nausea occurred in two patients (5.4 %), grade 3 fatigue in two patients (5.4 %), and grade 3 proteinuria in one patient (2.7 %). Toxicity during the switch maintenance treatment was mild: Two patients experienced grade 3 neutropenia, one patient experienced grade 3 thrombocytopenia, and another patient had grade 3 proteinuria and epistaxis (Table 4). No patient experienced grade 3 hypertension or venous thrombosis. Eleven (29.7 %) of the 37 patients had one or more dose reductions because of toxicity, and a total of five cycles were delayed for at least 1 week during induction chemotherapy. During maintenance therapy, no dose reduction or delay in Bev was required and a dose reduction in oral Vnb was needed for three patients.
Discussion This single-institution phase II study showed that induction therapy with Cis, Gem and Bev, followed by switch maintenance therapy with Bev and oral Vnb, was effective and well tolerated in patients with advanced non-squamous NSCLC. Although the current study did not meet its
Fig. 1 PFS and OS for the 37 enrolled patients
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Sensory neuropathy
4 (10.8 %)
0
0
Diarrhea Constipation
5 (13.5 %) 13 (35.1 %)
0 0
0 0
Hypertension
5 (13.5 %)
0
0
Proteinuria
18 (48.6 %)
1 (2.7 %)
0
Hemoptysis
2 (5.4 %)
0
0
Epistaxis
5 (13.5 %)
0
0
Table 4 Summary of adverse events during maintenance treatment Grade 2
Grade 3
8 (30.7 %)
2 (7.6 %)
Oral Vnb-associated Neutropenia Anemia
2 (7.6 %)
0
Thrombocytopenia
3 (11.5 %)
1 (3.8 %)
Nausea/vomiting
4 (15.3 %)
0
Abdominal pain
2 (7.6 %)
0
Diarrhea
2 (7.6 %)
0
Hypertension
4 (15.3 %)
0
Proteinuria
6 (23 %)
1(3.8 %)
Hemoptysis Epistaxis
2 (7.6 %) 3 (11.5 %)
0 1 (2.7 %)
Bev-associated
primary end point, the 45.9 % 9-month DCR, 8.4-month median PFS and 18.1-month median OS compared well with best results reported with conventional chemotherapy combined with Bev followed by Bev as maintenance. In this setting, although the AVAPERL trail showed a 3.7-month increase in PFS (7.4 vs 3.7 months) when using Bev/pemetrexed versus Bev alone as maintenance therapy, no significant difference in OS was observed between groups [18]. The PRONOUNCE trial recently reported that PFS without grade 4 toxicity was 3.9 months in patients receiving pemetrexed and carboplatin followed by pemetrexed versus 2.8 months in patients receiving paclitaxel, carboplatin and Bev followed by Bev; RR and OS were
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similar between treatment arms, too [19]. A recent retrospective analysis of patients treated in 17 community oncology practices across the USA showed that Bev maintenance therapy after initial chemotherapy contributed to OS benefit in NSCLC patients [20]. This study showed that the impact of Bev maintenance therapy on the overall HR for survival in a cohort of patients with advanced-stage NSCLC with non-squamous histology ranged from 0.44 to 0.78 with more than 30 % reduction in risk of death. There is a biologic rationale for a continued vascular endothelial growth factor suppression after an initial induction time period with Bev [21]. The continued secretion of VEGF by cancer cells interacts with the endothelial cells of existing blood vessels to promote the further formation of new blood vessels [22]. Mancuso et al. [23] have shown that when tumors were inhibited by VEGF tyrosine kinase receptor, the same tumors were completely re-vascularized within the first week after stopping treatment, suggesting a potential increase in tumor growth following withdrawal of VEGF inhibitors. Other agents were investigated as maintenance therapy in NSCLC patients. In the PARAMOUNT phase III randomized trial, pemetrexed as maintenance after four cycles of induction chemotherapy with Cis/pemetrexed demonstrated a slight improvement in PFS (4.1 vs 2.8 months) and OS (16.9 vs 14 months) compared to no maintenance treatment [24]. Recently, a phase III randomized trial compared maintenance therapy with either Gem or erlotinib after first-line therapy with Cis/Gem. Data showed that continuation maintenance therapy with single-agent Gem increased PFS to a greater extent (3.8 months) than switch maintenance therapy with erlotinib (2.9 months) when compared with observation (1.9 months) [25]. The ongoing ECOG5508 study (NCT01107626) is currently investigating different maintenance regimens containing Bev, pemetrexed or both, and results are eagerly awaited to clarify the optimal maintenance approach for patients with advanced NSCLC. However, although no definitive conclusions can be actually drawn, all available findings seem to suggest that Bev combined with chemotherapy may be a favorable choice as maintenance treatment in advanced NSCLC. In this setting, the combination of Bev with a safe and not expensive oral agent as Vnb we applied in our population study seems a valid treatment option which may be able to strike a balance between prolonged clinical response and mild toxicity. Nevertheless, although the comparison with large phase III trial is difficult, our results seem to be comparable with those reported in the aforementioned studies in which Bev was applied as maintenance. Other studies investigated oral Vnb alone as maintenance treatment in advanced NSCLC: 4.2-month median PFS and 10-month median OS were reported in 56 patients
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treated with oral Vnb as maintenance after Cis and oral Vnb as induction chemotherapy [26]. Another study documented 4.3-month median PFS and 9.7-month median OS in 57 patients with advanced NSCLC receiving oral Vnb as maintenance after carboplatin and oral Vnb as induction chemotherapy [27]. Therefore, by the comparison of our promising data with those reported in other similar phase II studies, it seems that Bev may add benefit to oral Vnb as maintenance treatment in terms of outcome improvement in advanced non-squamous NSCLC. Another point to consider is that the majority of studies enroll several patients\70–75 years and with good PS who do not reflect the majority of patients with advanced lung cancer in clinical practice. Our study included about 20 % of patients with ECOG PS 2, for whom concerns about toxicity may exist [28]. However, it was a small singleinstitution experience and definitive conclusions cannot be drawn. The treatment strategy we proposed exhibited a good safety profile: Grade 3 hematological adverse events were observed in only 10.8 % of patients during induction chemotherapy, and grade 4 was documented in only two patients. These favorable toxicity data are consistent with those reported with Cis/Gem and Bev combination when this chemotherapy regimen is administered for a limited number of cycles. Toxicities associated with Bev during maintenance treatment were consistent with the known adverse events associated with this drug, especially if administered for a long time period, and were grade 1–2 in the majority of cases. Finally, mainly due to the oral formulation, severe toxic effects related to oral Vnb were not observed. Nevertheless, single-agent Vnb has been reported to be extremely safe also in elderly patients with advanced NSCLC and impaired PS [29]. Besides activity, the well tolerability was one of the main reasons we chose oral Vnb as maintenance chemotherapy. In summary, switch maintenance treatment with Bev and oral Vnb after Cis, Gem and Bev is feasible in patients with advanced non-squamous NSCLC and may achieve encouraging results in terms of PFS and OS. These findings add to a growing body of evidence that maintenance with Bev combined with chemotherapy might prolong PFS in patients with advanced non-squamous NSCLC. Conflict of interest of interest.
The authors declare that they have no conflict
Ethical standard The study has been approved by the local institutional research ethical committee, and all procedures performed in human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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ORIGINAL PAPER
Switch maintenance treatment with oral vinorelbine and bevacizumab after induction chemotherapy with cisplatin, gemcitabine and bevacizumab in patients with advanced nonsquamous non-small cell lung cancer: a phase II study Roberto Petrioli1 • Edoardo Francini2 • Anna Ida Fiaschi3 • Letizia Laera1 Luca Luzzi4 • Piero Paladini4 • Claudia Ghiribelli4 • Luca Voltolini5 • Vincenzo Bianco2 • Giandomenico Roviello1
•
Received: 3 March 2015 / Accepted: 14 March 2015 / Published online: 22 March 2015 Ó Springer Science+Business Media New York 2015
Abstract The present study evaluated the efficacy and safety of cisplatin (Cis), gemcitabine (Gem) and bevacizumab (Bev), followed by maintenance treatment with Bev and oral vinorelbine (Vnb), in patients with advanced non-squamous non-small cell lung cancer (NSCLC). The patients were administered six cycles of induction chemotherapy consisting of intravenously (i.v.) Cis 70 mg/m2 on day 1 plus i.v. Gem 1000 mg/m2 on days 1 and 8, plus i.v. Bev 7.5 mg/kg on day 1, every 3 weeks. Patients who did not experience tumor progression remained on maintenance treatment with Bev combined with oral Vnb 60 mg/m2 weekly until occurrence of disease progression or unacceptable toxicity. Thirty-seven patients were enrolled: The median age was 67 years (range 38–81); 22 patients were male, and 30 patients had stage IV tumors. The response rate was 32.4 % (95 % CI 18–49.7). The 9-month disease-control rate was 45.9 %. The median PFS was 8.4 months (95 % CI 4.4–10.7), and the median OS was 18.1 months (95 % CI 15.3–20.8 months). Grade 3–4 neutropenia occurred in 6 (16.2 %) patients and grade 3–4
& Roberto Petrioli [email protected] 1
Medical Oncology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Bracci, 53100 Siena, Italy
2
Medical Oncology Unit, Policlinico Umberto I Hospital, University of Rome, Rome, Italy
3
Pharmacology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy
4
Unit of Thoracic Surgery, Surgery Department, University of Siena, Siena, Italy
5
Unit of Thoracic Surgery, Policlinico Careggi, University of Firenze, Florence, Italy
thrombocytopenia in four (10.8 %) patients during induction chemotherapy. Bev- or Vnb-associated toxicities were mild. Switch maintenance treatment with Bev and oral Vnb after first-line Cis, Gem and Bev is feasible in patients with non-squamous NSCLC and may achieve encouraging results in terms of PFS and OS. Keywords Bevacizumab Cisplatin Gemcitabine Maintenance Lung cancer Vinorelbine
Introduction Non-small cell lung cancer (NSCLC) is the most common malignancy and the leading cause of cancer death worldwide. Although surgical resection offers the only chance of long-term cure, the majority of NSCLC patients present with locally advanced or metastatic disease at diagnosis, and prognosis is very poor [1, 2]. Wild-type EGFR and ALK non-rearranged patients have to be treated with combination chemotherapy which usually includes cisplatin (Cis) or carboplatin, gemcitabine (Gem), taxanes, vinorelbine (Vnb), pemetrexed and antiangiogenic agents such as bevacizumab (Bev). Bev is a recombinant, humanised, monoclonal antibody against the vascular endothelial growth factor (VEGF) approved for the first-line treatment of advanced NSCLC [3–6]. The open-label Eastern Cooperative Oncology Group (ECOG) 4599 study showed that the addition of Bev to carboplatin–paclitaxel significantly extended overall survival (OS) and progression-free survival (PFS) and improved the objective response rate (RR) versus chemotherapy alone [5]. The double-blind AVAiL trial showed that Bev combined with Cis plus Gem improved the RR and significantly extended the PFS versus placebo, but the OS was not significantly
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different between the two treatment groups [6, 7]. In both trials, all of the patients were offered maintenance Bev until disease progression or unacceptable toxicity after six cycles of induction chemotherapy. The main rationale for using the antiangiogenic agent Bev as maintenance treatment is that tumor angiogenesis is critical for tumor progression. VEGF promotes angiogenesis, and overexpression of the VEGF has been correlated with poor prognosis in various malignancies, including NSCLC [8– 10]. However, despite the encouraging results obtained with combination chemotherapy followed by single-agent Bev as maintenance, prognosis of patients with advanced NSCLC remains poor, with PFS usually \6–7 months and median OS \15 months [6, 7]. In the search of improving the outcome of patients with advanced NSCLC, switch maintenance therapy is another possible option which provides a different agent that was not included as part of the first-line regimen. In this setting, Vnb is a chemotherapy agent which has showed activity and tolerability in lung cancer, and its oral formulation achieved promising results and good safety profile also in elderly patients [11–16]. The activity and tolerability of oral Vnb in patients with NSCLC was the main rationale for why this agent was chosen as maintenance chemotherapy in the current study. The aim of this a phase II study was to evaluate the activity and tolerability of a switch maintenance treatment consisting of Bev and oral Vnb in advanced non-squamous NSCLC patients after induction chemotherapy with Cis, Gem and Bev.
Patients and methods Eligibility criteria The study enrolled patients with histologically proven, measurable, stage IIIB or IV non-squamous NSCLC. No prior chemotherapy for advanced disease was allowed. The other eligibility criteria included age more than 18 years, ECOG performance status (PS) of 0–2, bidimensionally measurable disease, a life expectancy of at least 3 months, adequate hematological parameters (an absolute neutrophil count of C1.5 9 109/l and a platelet count of C100 9 109/ l), creatinine\1.5 times the upper limit of the normal range and total bilirubin levels \3 9 the upper normal limit, aspartate and alanine aminotransferase \3.0 9 the upper normal limit and the absence of a second primary tumor other than non-melanoma skin cancer or in situ cervical carcinoma. Exclusion criteria were histological evidence of predominant squamous cell cancer; a history of gross hemoptysis (C2.5 ml); brain metastases or prior treatment for brain metastasis; uncontrolled pleural or pericardial
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effusion or ascites; pregnancy or lactation; a history of documented hemorrhagic diathesis or coagulopathy; therapeutic anticoagulation; regular use of aspirin ([325 mg per day), non-steroidal antiinflammatory agents known to inhibit platelet function; radiation therapy within 21 days before enrollment or major surgery within 28 days before enrollment; clinically significant cardiovascular disease; and medically uncontrolled hypertension. This study was approved by the local ethical and scientific committee, and all of the patients gave their written informed consent. Patient evaluation Patients were seen at the start of every chemotherapy cycle for a physical examination, monitoring of symptoms and toxic effects, assessment of renal function and a complete blood count. After baseline evaluation, disease was reassessed every three cycles (approximately every 9 weeks) during induction chemotherapy. If patients withdrew from treatment for other reasons than progressive disease, follow-up tumor assessments were repeated every 2 months until disease progression. Objective tumor response was evaluated according to RECIST criteria. After completion of the induction chemotherapy, patients continued to have CT scans every 2 months for 6 months and thereafter at a 3-month interval until there was evidence of disease progression. Treatment delivery Patients received a maximum of six cycles of induction chemotherapy consisting of intravenously (i.v.) Cis 70 mg/ m2 on day 1 plus i.v. Gem 1000 mg/m2 on days 1 and 8, plus i.v. Bev at a dose of 7.5 mg/kg on day 1, every 3 weeks. Maintenance treatment consisted of Bev at a dose of 7.5 mg per kilogram on day 1 every 3 weeks and weekly oral Vnb 60 mg/m2. Toxicity Toxicity was assessed using the common toxicity criteria of the National Cancer Institute (NCI), version 2.0. Treatment was delayed if, on the planned day of treatment, the neutrophil count was \1500/mm3, the platelet count was\100,000/mm3 or the patient had persistent diarrhea or stomatitis [grade 1. Any patient who required more than 2 weeks for recovery from adverse reactions was excluded from the study. In the event of grade 4 hematological or any other severe (Cgrade 3) organ toxicity in individual patients, chemotherapeutic drug doses were reduced by 25 % for subsequent courses.
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Statistical considerations The primary end point was 9-month disease-control rate (DCR). A previous trial investigating Cis, Gem and Bev followed by Bev maintenance indicated that about 60 and 30 % of patients were progression-free 6 and 9 months after the start of treatment, respectively [6]. The hypothesis for the current study was that, using the combined Bev and oral Vnb as maintenance therapy, at least 50 % of patients would be progression-free 9 months after the start of chemotherapy. It was calculated that 39 patients would have to be recruited to yield a 80 % probability to correctly select the treatment when it is superior by absolute difference of 20 % in 9-month DCR [17]. PFS was calculated as the time from the first chemotherapy infusion to disease progression or death. Other secondary end points include safety, OS (measured from the date of the start of treatment to the date of death) and RR. Kaplan–Meier method was used to determine PFS and OS. Statistical analyses were conducted by STATAiC software.
Page 3 of 7 134 Table 1 Patient characteristics Characteristic
No. of patients (n = 37)
Age, years Median
67
Range
(38–81)
Sex Male
22
Female
15
ECOG PS 0
10
1
19
2
8
Disease stage IIIB IV
7 30
Surgery Yes
4
No
33
Radiotherapy Yes
4
No
33
Results Patient characteristics Between March 2011 and May 2014, 37 newly diagnosed patients with advanced non-squamous NSCLC were enrolled in the study. Baseline characteristics of the patients are presented in Table 1. In all, eight (21.6 %) patients had a PS of 2 and 30 (81.1 %) had stage IV. Four patients (10.8 %) had prior resection of their primary tumor with curative intent and were offered our treatment protocol after documentation of unresectable progressive or metastatic disease. All patients had not received any form of anticancer therapy for advanced disease; four patients had been previously treated with radiotherapy which had been stopped at least 6 months before entering in the study. Efficacy All of the 37 enrolled patients received three Cis/Gem/Bev treatment cycles (range 3–6 cycles) and were evaluable for response and toxicity. One patients (2.7 %) achieved complete remission and 11 (29.7 %) achieved partial remission, making the RR 32.4 % (95 % CI 18–49.7). Fourteen patients (37.8 %) achieved stable disease as their best response to therapy, and DCR was 70.2 % (95 % CI 53–84.1) (Table 2). Median duration of response to prior induction chemotherapy was 6.5 months (95 % CI 4.8–7.5).
Table 2 Best response to treatment Response
Cis/Gem/Bev ? Vnb/Bev
CR
1 (2.7 %)
PR
11 (29.7 %)
SD
14 (37.8 %)
PD
8 (21.6 %)
PR ? SD
12 (32.4 %)
9-month DCR
17 (45.9 %)
(95 % CI 16.7–56.6) (95 % CI 26.7–73.5) CR complete remission, PR partial remission, SD stable disease, PD progressive disease, DCR disease-control rate, Cis cisplatin, Gem gemcitabine, Bev bevacizumab, Vnb vinorelbine, CI confidence interval
The 26 patients who achieved DCR after induction chemotherapy with Cis/Gem/Bev received maintenance chemotherapy with oral Vnb and Bev for a median of 6 months (range 1–26 months). Twenty-two patients discontinued maintenance chemotherapy because of disease progression; one patient was lost to follow-up after 4 months from the onset of maintenance treatment; and three patients are still on maintenance treatment at the time of this writing. The 9-month DCR was 45.9 % (95 % CI 26.7–73.5). The median PFS time was 8.4 months (95 % CI 4.4–10.7).
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Eleven patients (29.7 %) received a second-line chemotherapy with pemetrexed, four patients were treated with docetaxel (10.8 %), and three patients (8.1 %) received a third-line chemotherapy with erlotinib. At a median follow-up of 19.2 months (range 5.5–26.4), a total of 30 patients were deceased: The median OS time was 18.1 months (95 % CI 15.3–20.8 months) (Fig. 1).
Med Oncol (2015) 32:134 Table 3 Summary of adverse events during induction chemotherapy Grade 2
Grade 3
Grade 4
Hematological Neutropenia
18 (48.6 %)
4 (10.8 %)
2 (5.4 %)
Anemia
23 (62.1 %)
1 (2.7 %)
0
Thrombocytopenia
24 (64.8 %)
2 (5.4 %)
2 (5.4 %)
Nausea
20 (54 %)
2 (5.4 %)
0
Vomiting
9 (24.3 %)
0
0
Fatigue
17 (45.9 %)
2 (5.4 %)
0
Stomatitis
6 (16.2 %)
0
0
Non-hematological
Treatment toxicity The incidence of toxicity during induction chemotherapy is summarized in Table 3. Grade 3–4 neutropenia occurred in six patients (16.2 %), grade 3–4 thrombocytopenia in four patients (10.8 %), and grade 3 anemia in one patient (2.7 %). Grade 3 nausea occurred in two patients (5.4 %), grade 3 fatigue in two patients (5.4 %), and grade 3 proteinuria in one patient (2.7 %). Toxicity during the switch maintenance treatment was mild: Two patients experienced grade 3 neutropenia, one patient experienced grade 3 thrombocytopenia, and another patient had grade 3 proteinuria and epistaxis (Table 4). No patient experienced grade 3 hypertension or venous thrombosis. Eleven (29.7 %) of the 37 patients had one or more dose reductions because of toxicity, and a total of five cycles were delayed for at least 1 week during induction chemotherapy. During maintenance therapy, no dose reduction or delay in Bev was required and a dose reduction in oral Vnb was needed for three patients.
Discussion This single-institution phase II study showed that induction therapy with Cis, Gem and Bev, followed by switch maintenance therapy with Bev and oral Vnb, was effective and well tolerated in patients with advanced non-squamous NSCLC. Although the current study did not meet its
Fig. 1 PFS and OS for the 37 enrolled patients
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Sensory neuropathy
4 (10.8 %)
0
0
Diarrhea Constipation
5 (13.5 %) 13 (35.1 %)
0 0
0 0
Hypertension
5 (13.5 %)
0
0
Proteinuria
18 (48.6 %)
1 (2.7 %)
0
Hemoptysis
2 (5.4 %)
0
0
Epistaxis
5 (13.5 %)
0
0
Table 4 Summary of adverse events during maintenance treatment Grade 2
Grade 3
8 (30.7 %)
2 (7.6 %)
Oral Vnb-associated Neutropenia Anemia
2 (7.6 %)
0
Thrombocytopenia
3 (11.5 %)
1 (3.8 %)
Nausea/vomiting
4 (15.3 %)
0
Abdominal pain
2 (7.6 %)
0
Diarrhea
2 (7.6 %)
0
Hypertension
4 (15.3 %)
0
Proteinuria
6 (23 %)
1(3.8 %)
Hemoptysis Epistaxis
2 (7.6 %) 3 (11.5 %)
0 1 (2.7 %)
Bev-associated
primary end point, the 45.9 % 9-month DCR, 8.4-month median PFS and 18.1-month median OS compared well with best results reported with conventional chemotherapy combined with Bev followed by Bev as maintenance. In this setting, although the AVAPERL trail showed a 3.7-month increase in PFS (7.4 vs 3.7 months) when using Bev/pemetrexed versus Bev alone as maintenance therapy, no significant difference in OS was observed between groups [18]. The PRONOUNCE trial recently reported that PFS without grade 4 toxicity was 3.9 months in patients receiving pemetrexed and carboplatin followed by pemetrexed versus 2.8 months in patients receiving paclitaxel, carboplatin and Bev followed by Bev; RR and OS were
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similar between treatment arms, too [19]. A recent retrospective analysis of patients treated in 17 community oncology practices across the USA showed that Bev maintenance therapy after initial chemotherapy contributed to OS benefit in NSCLC patients [20]. This study showed that the impact of Bev maintenance therapy on the overall HR for survival in a cohort of patients with advanced-stage NSCLC with non-squamous histology ranged from 0.44 to 0.78 with more than 30 % reduction in risk of death. There is a biologic rationale for a continued vascular endothelial growth factor suppression after an initial induction time period with Bev [21]. The continued secretion of VEGF by cancer cells interacts with the endothelial cells of existing blood vessels to promote the further formation of new blood vessels [22]. Mancuso et al. [23] have shown that when tumors were inhibited by VEGF tyrosine kinase receptor, the same tumors were completely re-vascularized within the first week after stopping treatment, suggesting a potential increase in tumor growth following withdrawal of VEGF inhibitors. Other agents were investigated as maintenance therapy in NSCLC patients. In the PARAMOUNT phase III randomized trial, pemetrexed as maintenance after four cycles of induction chemotherapy with Cis/pemetrexed demonstrated a slight improvement in PFS (4.1 vs 2.8 months) and OS (16.9 vs 14 months) compared to no maintenance treatment [24]. Recently, a phase III randomized trial compared maintenance therapy with either Gem or erlotinib after first-line therapy with Cis/Gem. Data showed that continuation maintenance therapy with single-agent Gem increased PFS to a greater extent (3.8 months) than switch maintenance therapy with erlotinib (2.9 months) when compared with observation (1.9 months) [25]. The ongoing ECOG5508 study (NCT01107626) is currently investigating different maintenance regimens containing Bev, pemetrexed or both, and results are eagerly awaited to clarify the optimal maintenance approach for patients with advanced NSCLC. However, although no definitive conclusions can be actually drawn, all available findings seem to suggest that Bev combined with chemotherapy may be a favorable choice as maintenance treatment in advanced NSCLC. In this setting, the combination of Bev with a safe and not expensive oral agent as Vnb we applied in our population study seems a valid treatment option which may be able to strike a balance between prolonged clinical response and mild toxicity. Nevertheless, although the comparison with large phase III trial is difficult, our results seem to be comparable with those reported in the aforementioned studies in which Bev was applied as maintenance. Other studies investigated oral Vnb alone as maintenance treatment in advanced NSCLC: 4.2-month median PFS and 10-month median OS were reported in 56 patients
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treated with oral Vnb as maintenance after Cis and oral Vnb as induction chemotherapy [26]. Another study documented 4.3-month median PFS and 9.7-month median OS in 57 patients with advanced NSCLC receiving oral Vnb as maintenance after carboplatin and oral Vnb as induction chemotherapy [27]. Therefore, by the comparison of our promising data with those reported in other similar phase II studies, it seems that Bev may add benefit to oral Vnb as maintenance treatment in terms of outcome improvement in advanced non-squamous NSCLC. Another point to consider is that the majority of studies enroll several patients\70–75 years and with good PS who do not reflect the majority of patients with advanced lung cancer in clinical practice. Our study included about 20 % of patients with ECOG PS 2, for whom concerns about toxicity may exist [28]. However, it was a small singleinstitution experience and definitive conclusions cannot be drawn. The treatment strategy we proposed exhibited a good safety profile: Grade 3 hematological adverse events were observed in only 10.8 % of patients during induction chemotherapy, and grade 4 was documented in only two patients. These favorable toxicity data are consistent with those reported with Cis/Gem and Bev combination when this chemotherapy regimen is administered for a limited number of cycles. Toxicities associated with Bev during maintenance treatment were consistent with the known adverse events associated with this drug, especially if administered for a long time period, and were grade 1–2 in the majority of cases. Finally, mainly due to the oral formulation, severe toxic effects related to oral Vnb were not observed. Nevertheless, single-agent Vnb has been reported to be extremely safe also in elderly patients with advanced NSCLC and impaired PS [29]. Besides activity, the well tolerability was one of the main reasons we chose oral Vnb as maintenance chemotherapy. In summary, switch maintenance treatment with Bev and oral Vnb after Cis, Gem and Bev is feasible in patients with advanced non-squamous NSCLC and may achieve encouraging results in terms of PFS and OS. These findings add to a growing body of evidence that maintenance with Bev combined with chemotherapy might prolong PFS in patients with advanced non-squamous NSCLC. Conflict of interest of interest.
The authors declare that they have no conflict
Ethical standard The study has been approved by the local institutional research ethical committee, and all procedures performed in human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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