Review Article
Immunotherapy in lung cancer Erminia Massarelli1, Vassiliki Papadimitrakopoulou1, James Welsh2, Chad Tang2, Anne S. Tsao1 1
Department of Thoracic Head and Neck Medical Oncology, 2Department of Radiation Oncology, the University of Texas MD Anderson Cancer
Center, Houston, TX, USA Correspondence to: Erminia Massarelli, M.D., Ph.D, M.S. Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030, USA. Email: [email protected].
Abstract: Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC. Keywords: Lung cancer; immunotherapy; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC); checkpoint inhibitors Submitted Dec 21, 2013. Accepted for publication Jan 17, 2014. doi: 10.3978/j.issn.2218-6751.2014.01.01 Scan to your mobile device or view this article at: http://www.tlcr.org/article/view/2068/2727
Introduction Lung cancer is the leading cause of cancer death in United States (1). Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5% (1). The use of molecular targeted therapies, such as erlotinib and crizotinib, has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations [epidermal growth factor receptor (EGFR) sensitizing mutations: 15-18% frequency in unselected NSCLC; anaplastic lymphoma kinase (ALK) tranlocations: 2-8% frequency in unselected NSCLC] (2,3). However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Immunotherapeutics can be defined as a broad class of therapies designated to elicit immune-mediated destruction
of tumor cells. Different approaches have been undertaken to stimulate immune response against cancer such as therapeutic vaccines, immunomodulators, autologous cellular therapies, monoclonal antibodies directed against checkpoint inhibitor signals on activated T cells and/or cancer cells. Historically, immunotherapy has had minimal success in lung cancer, resulting in the common belief that lung cancer is nonimmunogenic (4). However, there are many ways in which lung cancer cells are able to evade the immune system, including secretion of immunosuppressive cytokines, loss of major histocompatibility complex antigen expression and expression of molecules that inhibit T cell activation. Recent promising results have been reported with the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway with achievement of durable clinical responses with manageable toxicity also in previously heavily treated lung cancer patients. This article
© Translational lung cancer research. All rights reserved.
www.tlcr.org
Transl Lung Cancer Res 2014;3(1):53-63
Massarelli et al. Immunotherapy in lung cancer
54
Table 1 Summary of completed NSCLC immunotherapy trials Immunotherapy
Target
Pt No.
Stage
Results
Stage I-III disease MAGE-A3
MAGE-A3
182
IB/II following complete
HR for DFS =0.76 (95% CI: 0.48-1.21), HR for OS =0.81
resection
(95% CI: 0.47-1.40) with MAGE-A3 compared to SOC (5)
IIIB/IV after 1st line
3 yr. OS 31% for BLP-25 and 17% for BSC (P=0.035)
chemotherapy
Stage IIIB subset MS 30.6 months for BLP-25 vs.
Stage IIIB-IV disease BLP-25
MUC1
171
13.3 months for BSC (HR =0.548, 95% CI: 0.301-0.999) (6,7) Belagenpimatucel-L TGF-β2
75
II/IIIA/IIIB/IV after completion of therapy
vaccine doses group (P=0.0069) (8)
EGF
80
IIIB/IV after first-line
MS 11.7 months with GAR and 3.6 months with PAR
chemotherapy
(P=0.0002) (9)
Epidermal growth factor
TG4010 Ipilimumab
Nivolumab BMS-936559
MUC1 CTLA-4
PD-1 PD-L1
148 204
Superior MS for high vaccine doses group vs. low
st
IIIB/IV with 1 line
6-months PFS 43.2% for TG4010 vs. 35.1% for
chemotherapy
chemotherapy alone (P=0.307) (10)
IIIB/IV or recurrent disease Immune-related PFS 5.7 months for phased ipilimumab + in combination with
chemotherapy vs. 4.6 months for placebo +
first-line chemotherapy
chemotherapy (HR 0.72; P=0.05) (11)
296 (122 IV after completion of
OR in 6 (33%) out of 18 with squamous cell histology; OR
NSCLC) first-line chemotherapy
in 7 (12%) out of 56 with nonsquamous histology (12)
207 (75 IV after completion of
OR in 4 (11%) of 36 nonsquamous histology; OR in 1 (8%)
NSCLC) first-line chemotherapy
of 13 squamous histology (13)
BSC, best supportive care; GAR, good antibody response; HR, hazard ration; MS, median survival; NSCLC, non-small cell lung cancer; OR, overall response; PAR, poor antibody response; PFS, progression-free survival; Pt, patients; RR, response rate; SOC, standard of care.
Therapeutic cancer vaccination is an antigen-specific immunotherapy that primes the immune system to produce antigen-specific antibodies, CD4+ T helper cells and CD8+ cytotoxic T-lymphocytes against relevant tumorassociated antigens. Different types of immunoadjuvants are used, including phospholipid, aluminum formulation, viral vector, dendritic cells or liposome presentation. In this section we will review the different strategies of vaccination that are in the later stages of clinical development. Two vaccines (MAGE-A3 and liposomal-BLP25) are in clinical development for the treatment of potentially curable NSCLC. The others have been tested in stage IIIB-IV NSCLC (Table 1).
MAGE-A3 vaccine MAGE-A3 is an antigen specifically associated with various solid tumors, including NSCLC. It is a promising target for immunotherapy because it is almost exclusively expressed on the cell surface of cancer cells. Studies indicate that 17-50% of NSCLC tumors express MAGE-A3 on their surface and expression has been associated with a poor prognosis (5,14). The MAGE-A3 antigen-specific immunotherapeutic (ASCI) is composed of a recombinant fusion protein (MAGE-A3 and protein D of Hemophilus influenza) in combination with an immune-enhancing adjuvant system. In a double-blind, phase II study, 182 patients with MAGE-A3-positive resected stage IB/II NSCLC were randomly assigned to vaccine or placebo in a 2 : 1 ratio (Table 1) (5,15). Patients received five doses of MAGE-A3 ASCI or placebo once every three weeks followed by a maximum of eight consolidation doses given once every three months. The long-term analysis showed a positive trend for MAGE-A3 treatment in this setting, with a
© Translational lung cancer research. All rights reserved.
www.tlcr.org
will review the recent clinical trials of immunotherapeutic agents in NSCLC and SCLC. Immunotherapy in NSCLC Vaccines for stage I-III NSCLC
Transl Lung Cancer Res 2014;3(1):53-63
Translational lung cancer research, Vol 3, No 1 February 2014
nonsignificant but clinically relevant improvement in disease-free interval (DFI) [hazard ratio (HR) 0.75; 95% CI: 0.46-1.23; P=0.254], disease free survival (DFS) (HR 0.76; 95% CI: 0.48-1.21; P=0.248), and OS (HR 0.81; 95% CI: 0.47-1.40; P=0.454) in favor of the MAGE-A3 group. Overall treatment was very well tolerated, resulting in high therapy compliance. Based on the experience with MAGE-A3 immunotherapy in advanced melanoma, a gene expression analysis of the tumors identified a signature of immune-related genes that appeared to be associated with a high risk for relapse. In fact, patients without this signature had a 5% risk for relapse (15). This signature has been incorporated as a secondary endpoint in the phase III MAGRIT (MAGE-A3 as adjuvant non-small-cell lung cancer immunotherapy) study (16). The MAGRIT study screened more than 13,000 patients with resected stage IB-IIIA NSCLC for immunohistochemical expression of the MAGE-A3 antigen. Ultimately, 2,270 patients were accrued by October 2011 (17). Prior adjuvant chemotherapy was not an exclusion criterion. Patients were randomly assigned 2:1 to vaccine or placebo and therapy was administered three times a week for five weeks followed by every 12 weeks for eight doses (16). DFS is the primary endpoint and prospective validation of the predictive value of the gene signature is a co-primary endpoint. Results from this study are expected in mid to late 2013. Liposomal BLP25 MUC1 is a membrane-bound glycoprotein that becomes overexpressed and undergoes aberrant glycosylation with malignant transformation of diverse tumor types including NSCLC (18). Liposomal BLP25 (L-BLP25, Stimuvax) is a liposomal vaccine consisting of 25 amino acids from the immunogenic variable number of tandem-repeats region of MUC1 combined with an immunoadjuvant monophosphoryl lipid A in a liposomal delivery system (19). The compound was studied in a phase II multicenter randomized clinical trial with 171 patients with stable or responding stage IIIB (38%) or IV (62%) NSCLC after first-line chemotherapy or after chemoradiation (6). Patients were randomly assigned to L-BLP25 plus best supportive care (BSC) (n=88) or BSC alone (n=83) (6). Patients randomly assigned to the vaccine arm received a single low dose cyclophosphamide (300 mg/m 2) infusion followed three days later by the first of eight weekly subcutaneous doses of L-BLP25. At the discretion of the investigator, patients could also receive maintenance vaccine injections once every six weeks starting six weeks after the last weekly
© Translational lung cancer research. All rights reserved.
55
vaccination and continuing until disease progression. The primary endpoint of the study was OS. L-BLP25 was well tolerated, with the majority of adverse events consisting of mild flu-like symptoms and no reported increase in serious adverse events (L-BLP25 plus BSC 26.1% vs. BSC 36.1%). Efficacy results suggested a nonsignificant trend toward improved OS for patients who received L-BLP25 (17.4 vs. 13 months for BSC alone, adjusted HR: 0.739; 95% CI: 0.509-1.073; P=0.112). A post hoc analysis suggested that the benefit of L-BLP25 was confined to the 65 patients with stage IIIB disease who had chemotherapy and radiation therapy (adjusted HR 0.524; 95% CI: 0.261-1.052; P=0.069) with a trend toward improved two-year survival (60% vs. 36.7% for BSC). However, it should be noted that this analysis was not a prespecified endpoint of the study. Updated analyses suggested a continued trend toward improved survival for vaccinated patients (median OS 30.6 vs. 13.3 months) and no serious long-term safety issues. On the basis of these findings, a large international phase III START (Stimulating Targeted Antigenic Responses To NSCLC) trial randomly assigned 1,513 patients with unresectable stage IIIB NSCLC following definitive chemoradiation to L-BLP25 with BSC or placebo plus BSC (20). This study, with a primary endpoint of OS and using the phase II vaccine schedule, completed accrual in November 2011. A press release at the end of 2012 mentioned that the START trial failed to meet its primary endpoint of improved OS with L-BLP25 (25.6 vs. 22.3 months for placebo; P=0.123), although analysis of a predefined secondary endpoint did suggest that patients who received concurrent chemoradiation may have derived some benefit from the addition of the vaccine (median OS for concurrent chemoradiation followed by vaccine: 30.8 vs. 20.6 months for concurrent chemoradiation followed by placebo; P=0.016) (20). In Asia, the smaller phase III INSPIRE study, with a design and patient population similar to that of START, began enrollment in December 2009 and is ongoing (21). In the United States, an ongoing phase II study is examining the combination of L-BLP25 with bevacizumab after chemoradiation for stage III NSCLC (22). Vaccines for advanced NSCLC Belagenpumatucel-L Tr a n s f o r m i n g g r o w t h f a c t o r- b e t a ( T G F - β ) i s a multifunctional cytokine that works in normal and neoplastic cells to promote epithelial differentiation and inhibit cell growth (23). Elevated levels of TGF-β2 are
www.tlcr.org
Transl Lung Cancer Res 2014;3(1):53-63
Massarelli et al. Immunotherapy in lung cancer
56
known to be linked to immunosuppression in cancer patients and in advanced NSCLC have been associated with a more aggressive phenotype and poor survival (24). Belagenpumatucel-L is an allogeneic whole-cell vaccine derived from four irradiated NSCLC cell lines (two adenocarcinoma, one squamous, and one large cell), that have been transfected with a plasmid containing the TGF-β2 antisense trans-gene, which downregulates TGF- β2 (8). The efficacy and safety of belagenpumatucel-L was investigated in 75 patients with stage II-IV NSCLC in a phase II study. The patients received one of three dose levels of belagenpumatucel-L (1.25×107, 2.5×107, or 5×107 cells/ injection) administered as an intradermal injection once monthly or once every other month (8). No significant difference in serious adverse events was noted between dose cohorts, and the majority of adverse events were attributable to disease activity apart from flu-like symptoms, which were noted in 16% of patients. A partial response rate of 15% was achieved in a subgroup of 61 patients with stage IIIB-IV disease (across all dose levels) and 59% of all enrolled patients were free from disease progression at four months. In a subgroup analysis patients with both cellular and humoral immune response to the vaccine (n=11) had improved survival compared with those (n=24) classified as immune responsenegative: median 32.5 months versus 11.6 months (95% CI: 5.6-17.6; P=0.011) (25). In a subsequent phase II study that enrolled 20 patients with stage IV NSCLC, no partial or complete responses were noted. However, 14 of 20 patients had stable disease at four months and no new safety issues were noted (26). Belagenpumatucel-L was further investigated in the randomized phase III STOP trial compared to placebo as maintenance therapy after standard platinum doublet chemotherapy for stage III-IV NSCLC (27). The primary endpoint was OS and the study completed enrollment of more than 500 patients in mid-2012. Results from this study are awaited.
chemotherapy, were randomized 1:1 to receive the EGF vaccine plus BSC or BSC alone (9). After priming with cyclophosphamide (200 mg/m 2), patients in the vaccine group received the vaccine on day 1, 7, 14, 28 and monthly thereafter (9). A trend towards increased survival was observed in all vaccinated patients compared with controls, and the difference was statistically significant (P=0.0124) in the subgroup with age
Immunotherapy in lung cancer Erminia Massarelli1, Vassiliki Papadimitrakopoulou1, James Welsh2, Chad Tang2, Anne S. Tsao1 1
Department of Thoracic Head and Neck Medical Oncology, 2Department of Radiation Oncology, the University of Texas MD Anderson Cancer
Center, Houston, TX, USA Correspondence to: Erminia Massarelli, M.D., Ph.D, M.S. Department of Thoracic Head and Neck Medical Oncology, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030, USA. Email: [email protected].
Abstract: Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5%. The use of molecular targeted therapies has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations. However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Recent favorable results of newer trials of therapeutic vaccines and checkpoint inhibitors have proven against the common belief that lung cancer is nonimmunogenic. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown durable clinical responses with manageable toxicity. Several phase II and III clinical trials testing the association of different schedule of chemotherapy and immunotherapy or immunotherapy alone are ongoing in lung cancer and important results are expected in the near future. However, more studies are needed to understand the optimal combination of immunotherapeutic agents with chemotherapy and radiation therapy for the treatment of NSCLC and SCLC. Keywords: Lung cancer; immunotherapy; non-small cell lung cancer (NSCLC); small cell lung cancer (SCLC); checkpoint inhibitors Submitted Dec 21, 2013. Accepted for publication Jan 17, 2014. doi: 10.3978/j.issn.2218-6751.2014.01.01 Scan to your mobile device or view this article at: http://www.tlcr.org/article/view/2068/2727
Introduction Lung cancer is the leading cause of cancer death in United States (1). Survival rates for metastatic lung cancer including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are poor with 5-year survival of less than 5% (1). The use of molecular targeted therapies, such as erlotinib and crizotinib, has improved median overall survival (OS) in a limited group of NSCLC patients whose tumors harbor specific genetic alterations [epidermal growth factor receptor (EGFR) sensitizing mutations: 15-18% frequency in unselected NSCLC; anaplastic lymphoma kinase (ALK) tranlocations: 2-8% frequency in unselected NSCLC] (2,3). However for a large group of NSCLC and SCLC molecular alterations are not available to lead to direct targeted therapies. Immunotherapeutics can be defined as a broad class of therapies designated to elicit immune-mediated destruction
of tumor cells. Different approaches have been undertaken to stimulate immune response against cancer such as therapeutic vaccines, immunomodulators, autologous cellular therapies, monoclonal antibodies directed against checkpoint inhibitor signals on activated T cells and/or cancer cells. Historically, immunotherapy has had minimal success in lung cancer, resulting in the common belief that lung cancer is nonimmunogenic (4). However, there are many ways in which lung cancer cells are able to evade the immune system, including secretion of immunosuppressive cytokines, loss of major histocompatibility complex antigen expression and expression of molecules that inhibit T cell activation. Recent promising results have been reported with the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway with achievement of durable clinical responses with manageable toxicity also in previously heavily treated lung cancer patients. This article
© Translational lung cancer research. All rights reserved.
www.tlcr.org
Transl Lung Cancer Res 2014;3(1):53-63
Massarelli et al. Immunotherapy in lung cancer
54
Table 1 Summary of completed NSCLC immunotherapy trials Immunotherapy
Target
Pt No.
Stage
Results
Stage I-III disease MAGE-A3
MAGE-A3
182
IB/II following complete
HR for DFS =0.76 (95% CI: 0.48-1.21), HR for OS =0.81
resection
(95% CI: 0.47-1.40) with MAGE-A3 compared to SOC (5)
IIIB/IV after 1st line
3 yr. OS 31% for BLP-25 and 17% for BSC (P=0.035)
chemotherapy
Stage IIIB subset MS 30.6 months for BLP-25 vs.
Stage IIIB-IV disease BLP-25
MUC1
171
13.3 months for BSC (HR =0.548, 95% CI: 0.301-0.999) (6,7) Belagenpimatucel-L TGF-β2
75
II/IIIA/IIIB/IV after completion of therapy
vaccine doses group (P=0.0069) (8)
EGF
80
IIIB/IV after first-line
MS 11.7 months with GAR and 3.6 months with PAR
chemotherapy
(P=0.0002) (9)
Epidermal growth factor
TG4010 Ipilimumab
Nivolumab BMS-936559
MUC1 CTLA-4
PD-1 PD-L1
148 204
Superior MS for high vaccine doses group vs. low
st
IIIB/IV with 1 line
6-months PFS 43.2% for TG4010 vs. 35.1% for
chemotherapy
chemotherapy alone (P=0.307) (10)
IIIB/IV or recurrent disease Immune-related PFS 5.7 months for phased ipilimumab + in combination with
chemotherapy vs. 4.6 months for placebo +
first-line chemotherapy
chemotherapy (HR 0.72; P=0.05) (11)
296 (122 IV after completion of
OR in 6 (33%) out of 18 with squamous cell histology; OR
NSCLC) first-line chemotherapy
in 7 (12%) out of 56 with nonsquamous histology (12)
207 (75 IV after completion of
OR in 4 (11%) of 36 nonsquamous histology; OR in 1 (8%)
NSCLC) first-line chemotherapy
of 13 squamous histology (13)
BSC, best supportive care; GAR, good antibody response; HR, hazard ration; MS, median survival; NSCLC, non-small cell lung cancer; OR, overall response; PAR, poor antibody response; PFS, progression-free survival; Pt, patients; RR, response rate; SOC, standard of care.
Therapeutic cancer vaccination is an antigen-specific immunotherapy that primes the immune system to produce antigen-specific antibodies, CD4+ T helper cells and CD8+ cytotoxic T-lymphocytes against relevant tumorassociated antigens. Different types of immunoadjuvants are used, including phospholipid, aluminum formulation, viral vector, dendritic cells or liposome presentation. In this section we will review the different strategies of vaccination that are in the later stages of clinical development. Two vaccines (MAGE-A3 and liposomal-BLP25) are in clinical development for the treatment of potentially curable NSCLC. The others have been tested in stage IIIB-IV NSCLC (Table 1).
MAGE-A3 vaccine MAGE-A3 is an antigen specifically associated with various solid tumors, including NSCLC. It is a promising target for immunotherapy because it is almost exclusively expressed on the cell surface of cancer cells. Studies indicate that 17-50% of NSCLC tumors express MAGE-A3 on their surface and expression has been associated with a poor prognosis (5,14). The MAGE-A3 antigen-specific immunotherapeutic (ASCI) is composed of a recombinant fusion protein (MAGE-A3 and protein D of Hemophilus influenza) in combination with an immune-enhancing adjuvant system. In a double-blind, phase II study, 182 patients with MAGE-A3-positive resected stage IB/II NSCLC were randomly assigned to vaccine or placebo in a 2 : 1 ratio (Table 1) (5,15). Patients received five doses of MAGE-A3 ASCI or placebo once every three weeks followed by a maximum of eight consolidation doses given once every three months. The long-term analysis showed a positive trend for MAGE-A3 treatment in this setting, with a
© Translational lung cancer research. All rights reserved.
www.tlcr.org
will review the recent clinical trials of immunotherapeutic agents in NSCLC and SCLC. Immunotherapy in NSCLC Vaccines for stage I-III NSCLC
Transl Lung Cancer Res 2014;3(1):53-63
Translational lung cancer research, Vol 3, No 1 February 2014
nonsignificant but clinically relevant improvement in disease-free interval (DFI) [hazard ratio (HR) 0.75; 95% CI: 0.46-1.23; P=0.254], disease free survival (DFS) (HR 0.76; 95% CI: 0.48-1.21; P=0.248), and OS (HR 0.81; 95% CI: 0.47-1.40; P=0.454) in favor of the MAGE-A3 group. Overall treatment was very well tolerated, resulting in high therapy compliance. Based on the experience with MAGE-A3 immunotherapy in advanced melanoma, a gene expression analysis of the tumors identified a signature of immune-related genes that appeared to be associated with a high risk for relapse. In fact, patients without this signature had a 5% risk for relapse (15). This signature has been incorporated as a secondary endpoint in the phase III MAGRIT (MAGE-A3 as adjuvant non-small-cell lung cancer immunotherapy) study (16). The MAGRIT study screened more than 13,000 patients with resected stage IB-IIIA NSCLC for immunohistochemical expression of the MAGE-A3 antigen. Ultimately, 2,270 patients were accrued by October 2011 (17). Prior adjuvant chemotherapy was not an exclusion criterion. Patients were randomly assigned 2:1 to vaccine or placebo and therapy was administered three times a week for five weeks followed by every 12 weeks for eight doses (16). DFS is the primary endpoint and prospective validation of the predictive value of the gene signature is a co-primary endpoint. Results from this study are expected in mid to late 2013. Liposomal BLP25 MUC1 is a membrane-bound glycoprotein that becomes overexpressed and undergoes aberrant glycosylation with malignant transformation of diverse tumor types including NSCLC (18). Liposomal BLP25 (L-BLP25, Stimuvax) is a liposomal vaccine consisting of 25 amino acids from the immunogenic variable number of tandem-repeats region of MUC1 combined with an immunoadjuvant monophosphoryl lipid A in a liposomal delivery system (19). The compound was studied in a phase II multicenter randomized clinical trial with 171 patients with stable or responding stage IIIB (38%) or IV (62%) NSCLC after first-line chemotherapy or after chemoradiation (6). Patients were randomly assigned to L-BLP25 plus best supportive care (BSC) (n=88) or BSC alone (n=83) (6). Patients randomly assigned to the vaccine arm received a single low dose cyclophosphamide (300 mg/m 2) infusion followed three days later by the first of eight weekly subcutaneous doses of L-BLP25. At the discretion of the investigator, patients could also receive maintenance vaccine injections once every six weeks starting six weeks after the last weekly
© Translational lung cancer research. All rights reserved.
55
vaccination and continuing until disease progression. The primary endpoint of the study was OS. L-BLP25 was well tolerated, with the majority of adverse events consisting of mild flu-like symptoms and no reported increase in serious adverse events (L-BLP25 plus BSC 26.1% vs. BSC 36.1%). Efficacy results suggested a nonsignificant trend toward improved OS for patients who received L-BLP25 (17.4 vs. 13 months for BSC alone, adjusted HR: 0.739; 95% CI: 0.509-1.073; P=0.112). A post hoc analysis suggested that the benefit of L-BLP25 was confined to the 65 patients with stage IIIB disease who had chemotherapy and radiation therapy (adjusted HR 0.524; 95% CI: 0.261-1.052; P=0.069) with a trend toward improved two-year survival (60% vs. 36.7% for BSC). However, it should be noted that this analysis was not a prespecified endpoint of the study. Updated analyses suggested a continued trend toward improved survival for vaccinated patients (median OS 30.6 vs. 13.3 months) and no serious long-term safety issues. On the basis of these findings, a large international phase III START (Stimulating Targeted Antigenic Responses To NSCLC) trial randomly assigned 1,513 patients with unresectable stage IIIB NSCLC following definitive chemoradiation to L-BLP25 with BSC or placebo plus BSC (20). This study, with a primary endpoint of OS and using the phase II vaccine schedule, completed accrual in November 2011. A press release at the end of 2012 mentioned that the START trial failed to meet its primary endpoint of improved OS with L-BLP25 (25.6 vs. 22.3 months for placebo; P=0.123), although analysis of a predefined secondary endpoint did suggest that patients who received concurrent chemoradiation may have derived some benefit from the addition of the vaccine (median OS for concurrent chemoradiation followed by vaccine: 30.8 vs. 20.6 months for concurrent chemoradiation followed by placebo; P=0.016) (20). In Asia, the smaller phase III INSPIRE study, with a design and patient population similar to that of START, began enrollment in December 2009 and is ongoing (21). In the United States, an ongoing phase II study is examining the combination of L-BLP25 with bevacizumab after chemoradiation for stage III NSCLC (22). Vaccines for advanced NSCLC Belagenpumatucel-L Tr a n s f o r m i n g g r o w t h f a c t o r- b e t a ( T G F - β ) i s a multifunctional cytokine that works in normal and neoplastic cells to promote epithelial differentiation and inhibit cell growth (23). Elevated levels of TGF-β2 are
www.tlcr.org
Transl Lung Cancer Res 2014;3(1):53-63
Massarelli et al. Immunotherapy in lung cancer
56
known to be linked to immunosuppression in cancer patients and in advanced NSCLC have been associated with a more aggressive phenotype and poor survival (24). Belagenpumatucel-L is an allogeneic whole-cell vaccine derived from four irradiated NSCLC cell lines (two adenocarcinoma, one squamous, and one large cell), that have been transfected with a plasmid containing the TGF-β2 antisense trans-gene, which downregulates TGF- β2 (8). The efficacy and safety of belagenpumatucel-L was investigated in 75 patients with stage II-IV NSCLC in a phase II study. The patients received one of three dose levels of belagenpumatucel-L (1.25×107, 2.5×107, or 5×107 cells/ injection) administered as an intradermal injection once monthly or once every other month (8). No significant difference in serious adverse events was noted between dose cohorts, and the majority of adverse events were attributable to disease activity apart from flu-like symptoms, which were noted in 16% of patients. A partial response rate of 15% was achieved in a subgroup of 61 patients with stage IIIB-IV disease (across all dose levels) and 59% of all enrolled patients were free from disease progression at four months. In a subgroup analysis patients with both cellular and humoral immune response to the vaccine (n=11) had improved survival compared with those (n=24) classified as immune responsenegative: median 32.5 months versus 11.6 months (95% CI: 5.6-17.6; P=0.011) (25). In a subsequent phase II study that enrolled 20 patients with stage IV NSCLC, no partial or complete responses were noted. However, 14 of 20 patients had stable disease at four months and no new safety issues were noted (26). Belagenpumatucel-L was further investigated in the randomized phase III STOP trial compared to placebo as maintenance therapy after standard platinum doublet chemotherapy for stage III-IV NSCLC (27). The primary endpoint was OS and the study completed enrollment of more than 500 patients in mid-2012. Results from this study are awaited.
chemotherapy, were randomized 1:1 to receive the EGF vaccine plus BSC or BSC alone (9). After priming with cyclophosphamide (200 mg/m 2), patients in the vaccine group received the vaccine on day 1, 7, 14, 28 and monthly thereafter (9). A trend towards increased survival was observed in all vaccinated patients compared with controls, and the difference was statistically significant (P=0.0124) in the subgroup with age
