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SRL172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer: phase III results

      Abstract

      Background

      This open-label, randomised phase III study was designed to further investigate the clinical activity and safety of SRL172 (killed Mycobacterium vaccae suspension) with chemotherapy in the treatment of non-small-cell lung cancer (NSCLC).

      Patients and methods

      Patients were randomised to receive platinum-based chemotherapy, consisting ofup to six cycles of MVP (mitomycin, vinblastine and cisplatin or carboplatin) with (210 patients) or without (209 patients) monthly SRL172.

      Results

      There was no statistical difference between the two groups in overall survival (primary efficacy end point) over the course of the study (median overall survival of 223 days versus 225 days; P = 0.65). However, a higher proportion of patients were alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (90%), than in the chemotherapy alone group (83%) (P = 0.061). At the end of the treatment phase, the response rate was 37% in the combined group and 33% in the chemotherapy alone group. Patients in the chemotherapy alone group had greater deterioration in their Global Health Status score (–14.3) than patients in the chemotherapy plus SRL172 group (–6.6) (P = 0.02).

      Conclusion

      In this non-placebo controlled trial, SRL172 when added to standard cancer chemotherapy significantly improved patient quality of life without affecting overall survival times.

      Keywords

      Introduction

      Lung cancer is the most common cancer globally with >1 million new cases recorded each year [
      ]. About 80% of lung cancercases are classified as non-small-cell lung cancer (NSCLC). Approximately 30–40% of all patients with NSCLC have locally unresectable disease at the time of initial diagnosis (stage IIIa and stage IIIb) and 40–50% of all lung cancer patients have metastases at first presentation (stage IV) [
      • Jett J.R.
      Current treatment of unresectable lung cancer.
      ]. Patients presenting with late-stage disease (stage III or IV) have a poor prognosis with an overall 5-year survival rate of ∼5% in England and Wales, and 9% in Europe [
      Cancer Survival Trends. Office for National Statistics.
      ]. Despite changes in primary treatments, the mortality rates for patients with NSCLC have not improved significantly in the past 20 years [
      • Ginsberg R.J.
      • Vokes E.E.
      • Raben A.
      • De Vita V.T.
      • Hellman S.
      • Rosenberg S.A.
      Cancer: Principles and Practice of Oncology.
      ].
      Although advanced-stage NSCLC (stage IIIb/IV) remains a non-curable disease, chemotherapy has been shown to increase symptom control, improve quality of life, be cost-effective and increase survival rates (median and 1-year) [
      • Non-small Cell Lung Cancer Collaborative Group
      Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials.
      ]. Most patients newly diagnosed with late-stage NSCLC and a good performance status will be treated with chemotherapy. Modern platinum combination chemotherapy regimens produced an overall response rate of ∼20% with a median survival of 7.9 months and 1-year survival of 33% [
      • Schiller J.H.
      • Harrington D.
      • Belani C.P.
      • et al.
      Comparing regimens for nonsmall-cell lung cancer (ECOG Trial).
      ]. In the UK MIC2 study, chemotherapy provided overall response rates of 33%, 1-year survival of 26% and median survival of ∼7 months [
      • Cullen M.H.
      • Billingham L.J.
      • Woodroffe C.M.
      • et al.
      Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life.
      ].
      SRL172 is a suspension of killed Mycobacterium vaccae, a rapidly growing mycobacterium that normally grows as an environmental saprophyte. It has several functions relevant to its activity in cancer, including activation of antigen-presenting cells (APCs), Th1 adjuvant properties, suppression of pre-existing Th2 responses (via activation of regulatory T cells), and activation of natural killer (NK) cells [
      • Mendes R.
      • O’Brien M.E.R.
      • Mitra A.
      • et al.
      Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy inpatients with malignant mesothelioma.
      ]. A switch to a Th2 cytokine profile in cancer has been described, for example, in colorectal cancer [
      • Pellegrini P.
      • Berghella A.M.
      • Del Beato T.
      • et al.
      Dysregulation in Th1 and Th2 subsets of CD4+ T cells in peripheral blood of colorectal cancer patients and involvement in cancer establishment and progression.
      ], NSCLC [
      • Huang M.
      • Wang J.
      • Lee P.
      • et al.
      Human non-small cell lung cancer cells express a type 2 cytokine pattern.
      ] and small-cell lung cancer (SCLC) [
      • Fischer J.R.
      • Schindel M.
      • Bulzebruck H.
      • et al.
      Decrease of interleukin-2 secretion is a new independent prognostic factor associated with poor survival in patients with small-cell lung cancer.
      ].
      The activity of SRL172 in various forms of cancer has been suggested in a number of phase I and II clinical studies in malignant melanoma [
      • Maraveyas A.
      • Baban B.
      • Kennard D.
      • et al.
      Possible improved survival of patients with stage IV AJCC melanoma receiving SRL172 immunotherapy: correlation with induction of increased levels of intracellular interleukin-2 in peripheral blood lymphocytes.
      ], mesothelioma [
      • Mendes R.
      • O’Brien M.E.R.
      • Mitra A.
      • et al.
      Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy inpatients with malignant mesothelioma.
      ] and prostate cancer [
      • Hrouda D.
      • Baban B.
      • Dunsmuir W.D.
      • et al.
      Immunotherapy of advanced prostate cancer: a phase I/II trial using Mycobacterium vaccae (SRL172). Br J.
      ]. This current study was designed following initial results suggesting a 29% survival benefit in a small randomised phase II study in NSCLC [
      • O’Brien M.E.R.
      • Saini A.
      • Souberbielle B.E.
      • et al.
      A randomised phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small cell lung cancer and mesothelioma.
      ] and a similar result in SCLC [
      • Assersohn L.
      • Souberbielle B.E.
      • O’Brien M.E.R.
      • et al.
      A randomised pilot study of SRL172 (Mycobacterium vaccae) in patients with small cell lung cancer (SCLC) treated with chemotherapy.
      ]. These studies raised the possibility of synergy between chemotherapy and SRL172. This trial aimed to investigate the efficacy and safety of SRL172 in the treatment of patients with surgically unresectable locally advanced or metastatic NSCLC, when given in addition to standard chemotherapy.

      Patients and methods

       Study design

      The study design was based on experience gained from previous phase I/II studies conducted with SRL172. The study was designed as a randomised but open trial as SRL172 is a suspension and most patients develop a delayed-type hypersensitivity reaction at the injection site, making the use of a matching placebo difficult. Since the primary end point was overall survival, observer bias was considered to be negligible. In addition, randomisation was blinded, thereby avoiding bias in the allocation of individual patients to treatment. Patients were stratified by extent of disease as either surgically unresectable stage IIIa, or stage IIIb/IV (palliative treatment). The study was conducted at a total of 28 sites in four countries: Austria (three sites), Germany (five sites), Poland (four sites) and the UK (16 sites).
      The protocol and its amendments were approved by the appropriate Independent Ethics Committee (IEC) for each participating centre. The study was conducted in accordance with the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and with the principles stated in the Declaration of Helsinki. Written informed consent was obtained from all patients.

       Patient selection

      Male or female patients aged at least 18 years, with histologically and/or cytologically confirmed unresectable NSCLC (stages IIIa, IIIb and IV) were eligible for the study. Patients were to have measurable lesions in at least one site, which had not been previously irradiated, an European Organisation for Research and Treatment of Cancer–World Health Organisation (EORTC–WHO) performance status of <2 and life expectancy of >3 months in the opinion of the investigator.
      Patients were excluded if they had severe, active, uncontrolled infection requiring systemic antibiotics, antivirals or antifungals; if they had received previous chemotherapy for NSCLC; if they had evidence of central nervous system (CNS) metastases or if they had any previous or concurrent malignancy (except adequately treated carcinoma in situ of the cervix, basal cell carcinoma of the skin and/or non-melanoma skin cancer or if previous malignancy was more than 5 years prior and there were no signs of recurrence). They must not have received depot corticosteroids in the 6 weeks prior to day 0 or chronic systemic corticosteroids in the 2 weeks prior to administration of the study drug. Patients who had previously received SRL172 were also excluded.

       Treatment schedule

      Patients were screened to ensure that 400 evaluable patients were enrolled. Following a screening period of up to 28 days, those who fulfilled the entry criteria and had given written informed consent were stratified by extent of disease as either surgically unresectable stage IIIa or stage IIIb/IV. These patients were then randomised to receive either chemotherapy alone or chemotherapy plus SRL172. Chemotherapy consisted of up to six cycles of MVP [mitomycin C 8–10 mg/m2; vinblastine 6 mg/m2 (max 10 mg) and cisplatin 50–120 mg/m2 or carboplatin AUC of 4–6 (mg/ml × min) × (EDTA + 25)] on day 0 and weeks 3, 6, 9, 12 and 15. The doses used were according to the standard protocol at each centre, and mitomycin C was excluded at cycles three and five.

       SRL172 administration

      SRL172 (a suspension of heat-killed M. vaccae NCTC 11659) was supplied in borate-buffered saline at pH 8, 0.1 ml of which contained 1 mg wet weight corresponding to 109 bacilli. A dose of 0.1 ml was given intradermally over the deltoid muscle on day 0 and weeks 4, 8, 12 and 16 during the treatment phase. The vials of SRL172 were supplied and kept in refrigrators at 4°C.
      The four phases of the study are illustrated in Figure 1. If there was no disease progression after the initial treatment phase, patients randomised to receive SRL172 entered a maintenance and follow-up phase, during which they could continue to receive SRL172 and were clinically assessed every 8 weeks, until there was clear evidence of disease progression. The patients randomised to receive chemotherapy alone entered a follow-up phase during which they were clinically assessed every 8 weeks, until there was clear evidence of disease progression. After disease progression, patients entered the survival phase of the study during which they were clinically assessed every 12 weeks.
      Figure 1
      Figure 1The four phases of the study. PD, progressive disease.

       Evaluation criteria

      Overall survival (time from randomisation to death) was the primary end point of the study. Secondary efficacy variables included the proportion of patients who were alive 1 year after randomisation, various tumour response parameters, proportion of patients suitable for treatment downstaging after completion of study medication, progression-free survival and subgroup analysis as appropriate. Safety criteria related to disease, chemotherapy and SRL172 were also evaluated. In addition, treatment differences in health-related quality of life were investigated for the treatment and maintenance phases combined and treatment differences in health-related quality of life for the treatment phase, maintenance and survival phase and the end-of-study.

       Statistical analysis

      Survival. The sample size requirements for this study were based on the comparison planned for the primary efficacy parameter, overall survival time. Preliminary results from a pilot study [
      • O’Brien M.E.R.
      • Saini A.
      • Souberbielle B.E.
      • et al.
      A randomised phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small cell lung cancer and mesothelioma.
      ] indicated an increase in median overall survival time from 7 months (MVP-treated patients) to 9.5 months (MVP plus SRL172), i.e. a median survival time ratio of ∼1.4. Estimates from the literature suggested a 1-year survival rate for MVP-treated patients of ∼10%. Combining these estimates yielded an estimated 1-year survival rate for chemotherapy plus SRL172 patients of ∼20%. Thus, allowing for a 10% drop out, 80% power and a significance level of 0.02; 200 patients per group (i.e. 400 evaluable patients) were enrolled into the study.
      The overall survival curves were compared using a stratified Mantel Haenszel test and Kaplan–Meier plots of the survival times were performed. The analyses used all information up to the date of death. Patients were censored at the last date they were known to be alive (i.e. last assessment date). Each disease stage was also analysed separately in the same manner. Dichotomous efficacy variables (i.e. proportions of patients with an event) were compared between treatment groups using Fisher’s exact test and corresponding 95% confidence interval. Time-to-event variables were compared between treatment groups using a Mantel Haenszel test, with presentation of summary statistics derived from Kaplan–Meier estimates. Duration of event variables were compared between treatment groups using a Wilcoxon rank sum test.
      Summary statistics were generated for other efficacy and safety variables. Additional exploratory analyses were conducted, using accelerated failure time (AFT) modelling, to evaluate the influence of covariates on survival time. Subgroup analyses were performed of overall survival and the proportion of patients alive at the end of the treatment phase.
      Quality of life. The Global Health Status scale was the primary scale examined for significant treatment differences at the 0.05 level of significance. The null hypothesis was that there was no statistical difference between active treatment groups. Individual scale scores were examined for differences, adjusting for multiplicity using the Hochberg–Benjamini sequential testing procedure. EORTC assessments were scored according to standard rules as described in the EORTC QLQ–C30 (EORTC Quality of Life Questionnaire–Core 30) Scoring Manual [

      P Fayers, N Aaronson, K Bjordal et al. on behalf of EORTC Quality of Life Study Group. EORTC QLQ–C30 Scoring Manual.

      ]. All of the scales and single-item measures ranged in score from 0 to 100. A high scale score represented a higher response level (e.g. high score for a functional scale represented a high level of functioning and a high score for a symptom scale represented a high level of symptomatology/problems). The primary quality of life analysis was the evaluation of longitudinal scores in the chemotherapy plus SRL172 group, compared with the chemotherapy alone group using generalised estimating equations, adjusting for covariates.

      Results

       Demographic data

      The demographic data at screening for all randomised patients is summarised in Table 1, whilst Table 2 summarises the key data regarding NSCLC history. Examination of demographic and other baseline data did not reveal any clinically relevant differences between the treatment groups.
      Table 1Demographic data at screening: all randomised patients
      VariableChemotherapy + SRL172 (n = 210)Chemotherapy alone (n = 209)Total (n = 419)
      Sex
       Male149 (71%)151 (72%)300 (72%)
       Female61 (29%)58 (28%)119 (28%)
      Race
       Caucasian210 (100%)205 (98%)415 (99%)
       Black01 (0.5%)1 (0.25%)
       Asian02 (1%)2 (0.5%)
       Other01 (0.5%)1 (0.25%)
      Age, years
       Median (range)61.0 (40.0–78.0)62.0 (30.0–78.0)61.0 (30.0–78.0)
      Table 2NSCLC history at screening: all randomised patients
      VariableChemotherapy + SRL172
      One patient with chemotherapy + SRL172 had more than one NSCLC histology sub-type.
      ,
      Two patients with chemotherapy + SRL172 and one patient with chemotherapy alone had no NSCLC histology sub-type and were included in the category ‘Other’.
      Chemotherapy alone
      Two patients with chemotherapy + SRL172 and one patient with chemotherapy alone had no NSCLC histology sub-type and were included in the category ‘Other’.
      Total
      One patient with chemotherapy + SRL172 had more than one NSCLC histology sub-type.
      ,
      Two patients with chemotherapy + SRL172 and one patient with chemotherapy alone had no NSCLC histology sub-type and were included in the category ‘Other’.
      Histologyn = 208n = 208n = 416
       Squamous cell carcinoma89 (43%)82 (39%)171 (41%)
       Adenocarcinoma69 (33%)75 (36%)144 (35%)
       Large cell carcinoma27 (13%)29 (14%)56 (13%)
       Other24 (12%)22 (11%)46 (11%)
      Disease stagen = 210n = 209n = 419
       IIIa18 (9%)23 (11%)41 (9.8%)
       IIIb61 (29%)67 (32%)128 (30.5%)
       IV131 (62%)119 (57%)250 (59.7%)
      Previous surgeryn = 210n = 209n = 419
       Yes32 (15%)27 (13%)59 (14%)
       No178 (85%)182 (87%)360 (86%)
      Previous radiotherapyn = 210n = 209n = 419
       Yes23 (11%)15 (7%)38 (9%)
       No187 (89%)194 (93%)381 (91%)
      Time since diagnosis of NSCLC (days)n = 209n = 209n = 418
       Median25.022.023.0
       Minimum1.01.01.0
       Maximum1384.01344.01384.0
      NSCLC, non-small-cell lung cancer.
      a One patient with chemotherapy + SRL172 had more than one NSCLC histology sub-type.
      b Two patients with chemotherapy + SRL172 and one patient with chemotherapy alone had no NSCLC histology sub-type and were included in the category ‘Other’.
      A total of 210 patients were randomised to receive chemotherapy plus SRL172 and 209 patients were randomised to receive chemotherapy alone. Evaluable patients were defined as those who were randomised to receive study drug, received at leastone administration of either the standard chemotherapy regimen (208 patients) and/or at least one administration of SRL172 (208 patients), had NSCLC and reported data for analysis. Data from patients who became ineligible for the study were censored at the time of protocol violation or deviation.
      The majority of patients enrolled were male (71% overall) and the median age was 61 years. The most frequent histology, reflecting the fact that this was a European study, was squamous cell carcinoma (41%), followed by adenocarcinoma (35%), large cell carcinoma (13%) and other types of carcinoma (11%) [
      • Mendes R.
      • O’Brien M.E.R.
      • Mitra A.
      • et al.
      Clinical and immunological assessment of Mycobacterium vaccae (SRL172) with chemotherapy inpatients with malignant mesothelioma.
      ].

       Primary efficacy analysis

      The primary efficacy end point for this study was overall survival. The Kaplan–Meier plot of overall survival is presented in Figure 2. No difference was observed between the treatment groups in overall survival, with a median survival time of 223 days in the chemotherapy plus SRL172 group, compared to 225 days in the chemotherapy alone group (P = 0.65).
      Figure 2
      Figure 2Kaplan–Meier plot of overall survival.
      There was a trend towards a higher proportion of patients alive at the end of the 15-week treatment phase (Figure 2) in the chemotherapy plus SRL172 group (90%) than in the chemotherapy alone group (83%, P = 0.061).
      In this context it is of note that only 46% of patients randomised to the chemotherapy plus SRL172 group received the scheduled number of doses during the treatment phase and 63% of patients did not receive any further injections of SRL172 after the end of the 15-week treatment phase. The mean number of SRL172 injections overall was 4.7 for all patients in the SRL172 group. Also, only 27% of patients in the chemotherapy plus SRL172 group and 28% of patients in the chemotherapy alone group received six courses of MVP. Seventy-seven per cent of patients received three or more MVP courses in this study.

       Secondary efficacy analyses

      The results from the secondary efficacy analyses were in general in accordance with the results of the primary analysis. None of the prospectively defined secondary efficacy analyses were statistically significant, although there was a trend towards improved time to progression for the chemotherapy plus SRL172 group compared to the chemotherapy alone group (158 days versus 135 days, P = 0.1556).
      Overall, in each of the treatment groups, 26% of patients were alive at 1 year. There was a slightly higher proportion of patients alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (186 patients, 90%), than in the chemotherapy alone group (174 patients, 83%). This difference just failed to achieve statistical significance (P = 0.061).
      Similar proportions of patients in each treatment group had an objective tumour response during the study (chemotherapy plus SRL172, 37%; chemotherapy alone, 33%) (P = 0.413). There was no significant difference between the treatment groups in the time to an objective tumour response. The median time from objective tumour response to progression was 172 days in the chemotherapy plus SRL172 group and 150 days in the chemotherapy alone group (P = 0.1653). There was no difference between the treatment groups in the time from disease progression to death.
      There was no statistically significant difference in survival in different subgroups (male versus female and performance status 0/1 versus 2), although a trend was seen in adenocarcinomas (193 days survival with chemotherapy plus SRL172 compared with 154 days for chemotherapy alone; P = 0.10, 144 patients).

       Quality of life

      At the end of the 15-week treatment phase, there was a statistically significant difference in the mean change from baseline in the primary quality of life variable, Global Health Status, betweenthe treatment groups (adjusted P-value 0.002), with patients in the chemotherapy alone group (172 patients) having a greater deterioration in their Global Health Status score (–14.3) than patients in the chemotherapy plus SRL172 group (179 patients) (–6.6). Two methods were used in the analysis: Multiple Imputational Analysis (MIA) (43% imputed) and Last Observation Carried Forward (LOCF) (39% carried forward). Both techniques gave similar results.
      Mean changes from baseline (179 patients) in EORTC QLQ–C30 composite scores in the chemotherapy plus SRL172 group, compared to the chemotherapy alone group, at the end of the treatment phase are presented in Table 3. Missing values in this analysis were accounted for by MIA. Statistically significant differences at the end of the treatment phase were noted in favour of the chemotherapy plus SRL172 group in all other composite components of the QLQ–C30 questionnaire, except ‘role limited due to physical problems’ and ‘social functioning’ where differences were not statistically significant. Statistically significant differences at the end of the treatment phase were also noted in favour of the chemotherapy plus SRL172 group for many of the single items on the QLQ–C30 questionnaire.
      Table 3Analysis at end of 15-week treatment phase on composite scores from EORTC QLQ–C30 (multiple imputation)
      TreatmentSample sizeRaw mean changefrom baselineAdjusted mean changefrom baseline
      Mean change and P values adjusted for age, sex, current smoking status, cancer stage, weight loss and country. Mean change also adjusted for baseline.
      Raw SDP valueunadjustedP valueadjusted
      Mean change and P values adjusted for age, sex, current smoking status, cancer stage, weight loss and country. Mean change also adjusted for baseline.
      1. Global Health Status
       Chemo only172–14.2087–14.346225.98870.0070.002
       Chemo + SRL172179–6.7368–6.627125.0216
      2. Physical functioning
       Chemo only169–24.5853–27.745026.50440.0100.002
       Chemo + SRL172178–16.8608–18.974924.6951
      3. Role limited due to physical problems
       Chemo only170–16.5159–21.172735.83950.5790.120
       Chemo + SRL172178–14.1684–14.647434.5462
      4. Social functioning
       Chemo only172–15.0322–17.589036.51650.4130.120
       Chemo + SRL172180–11.8696–12.211930.4944
      5. Role limited due to emotional health
       Chemo only172–8.9916–12.558332.71430.0080.001
       Chemo + SRL1721800.5039–1.478827.6059
      6. Cognitive functioning
       Chemo only172–17.7260–21.630532.19910.0060.001
       Chemo + SRL172180–6.1101–8.647028.3704
      7. Bodily pain
       Chemo only17212.405813.418934.55250.0080.001
       Chemo + SRL1721800.8010–0.750333.7000
      8. Vitality
       Chemo only17219.361921.084928.19910.2370.021
       Chemo + SRL17218014.583014.231827.3624
      9. Nausea and vomiting
       Chemo only17224.998424.944532.54580.0080.011
       Chemo + SRL17218014.404115.216329.5638
      Note: for Global Health Status and the functioning parameters (parameters 1–6 above), a decrease from baseline indicates worsening. For the symptom parameters (parameters 7–9 above), a decrease from baseline indicates improvement.
      For all parameters except Global Health Status, the P values presented are the Hochberg–Benjamini P values.
      a Mean change and P values adjusted for age, sex, current smoking status, cancer stage, weight loss and country. Mean change also adjusted for baseline.
      By the end of the maintenance and survival phase, the differences observed at the end of the treatment phase in favour of the chemotherapy plus SRL172 group had diminished. Only subjects who had completed the treatment and maintenance phases and then entered the survival phase were included in this analysis. Hence sample sizes were small (chemotherapy alone, 28 patients; chemotherapy plus SRL172, 38 patients), resulting in a lack of statistical power in the MIA analyses. However, using the LOCF-imputed data, there was a statistically significant difference between treatments in favour of the chemotherapy plus SRL172 group for the primary parameter of Global Health Status, during the treatment and maintenance phase. Mean changes from baseline in scores from the EORTC QLQ–LC13 lung module, in the chemotherapy plus SRL172 group compared to the chemotherapy alone group, at the end of the treatment phase are presented in Table 4.
      Table 4Analysis at end of 15-week treatment phase on scores from EORTC QLQ–LC13 lung module (multiple imputation)
      TreatmentSample sizeRaw mean changefrom baselineAdjusted mean changefrom baseline
      Mean change and P values adjusted for age, sex, current smoking status, cancer stage, weight loss and country. Mean change also adjusted for baseline.
      Raw SDP valueunadjustedP valueadjusted
      Mean change and P values adjusted for age, sex, current smoking status, cancer stage, weight loss and country. Mean change also adjusted for baseline.
      Composite: bodily pain
       Chemo only15712.169913.622929.73850.1560.054
       Chemo + SRL1721706.25606.675627.9280
      Composite: dyspnoea
       Chemo only15717.243915.176330.23410.2780.110
       Chemo + SRL17217012.01878.782827.3841
      Q31: coughing
       Chemo only1574.925311.535534.18220.7210.161
       Chemo + SRL1721703.23605.185331.1033
      Q32: haemoptysis
       Chemo only15712.866814.287530.13480.2780.161
       Chemo + SRL1721707.45187.581927.6061
      Q36: sore mouth
       Chemo only15723.172722.212637.65970.0820.008
       Chemo + SRL17217014.58509.765030.4457
      Q37: dysphagia
       Chemo only15719.664920.171436.38730.0450.018
       Chemo + SRL17217010.017510.597429.7877
      Q38: peripheral neuropathy
       Chemo only15726.483931.552335.88370.0100.004
       Chemo + SRL17217013.637717. 967827.3152
      Q39: alopecia
       Chemo only15731.519235.274030.36230.5420.680
       Chemo + SRL17217029.102533.888528.5280
      Note: a decrease from baseline indicates improvement.
      The P values presented are the Hochberg–Benjamini P values.
      a Mean change and P values adjusted for age, sex, current smoking status, cancer stage, weight loss and country. Mean change also adjusted for baseline.
      At the end of the treatment phase, patients’ scores on all components of the QLQ–LC13 questionnaire had worsened from baseline in both treatment groups, as illustrated for the primary parameter of Global Health Status in Figure 3. However, the deterioration was less pronounced for the chemotherapy plus SRL172 group and treatment differences (adjusted) were statistically significant for sore mouth, dysphagia and peripheral neuropathy.
      Figure 3
      Figure 3Global Health Status change over time.

       Safety analyses

      A total of 192 patients (91.4%) in the chemotherapy plus SRL172 group reported at least one on-treatment, non-serious adverse event (AE) compared with 177 patients (84.7%) in the chemotherapy alone group. One hundred and six patients (50.5%) inthe chemotherapy plus SRL172 group reported at least one on-treatment serious adverse event (SAE), versus 80 patients (38.3%) in the chemotherapy alone group. In total, 1229 treatment emergent events (AE and SAE) were reported in the chemotherapy plus SRL172 group compared with 1034 events in the chemotherapy alone group.
      The most frequently occurring events (serious and non-serious) in both treatment groups were anaemia, leucopenia and thrombocytopenia, which were reported by 33.8%, 26.2% and 22.9% of patients in the chemotherapy plus SRL172 group and 25.8%, 23.4% and 16.3% of patients in the chemotherapy alone group, respectively. The differences were not statistically significant. The majority of these types of events were considered by the investigator not to be related to SRL172. A total of 35 patients (16.7%) in the chemotherapy plus SRL172 group reported an injection site reaction. However, in the majority of cases injection site reactions were of a mild intensity, with severe reactions reported in only two patients (1%) overall. There were more patients with NSCLC in the chemotherapy plus SRL172 group who reported chest pain (11%) than in the chemotherapy alone group (4%). However, only one case of chest pain in the chemotherapy plus SRL172 group was considered to be severe, compared to two cases in the chemotherapy alone group. None of the cases of chest pain were considered by the investigator to be related to study medication.
      No significant differences between treatment groups were observed in the incidence of abnormal laboratory values, vital signs, physical examination, tumour-related symptoms or chemotherapy toxicities.

      Discussion

      The overall results of the study did not show any difference in survival between those patients receiving standard chemotherapy and those additionally receiving SRL172, despite a survival trend in favour of the combined treatment group during the 15-week treatment phase (90% versus 83%, P = 0.061) and improved quality of life in the combined group. These results do not confirm those suggested in a small randomised phase II study [
      • O’Brien M.E.R.
      • Saini A.
      • Souberbielle B.E.
      • et al.
      A randomised phase II study of SRL172 (Mycobacterium vaccae) combined with chemotherapy in patients with advanced inoperable non-small cell lung cancer and mesothelioma.
      ] of 29 patients with symptomatic advanced NSCLC or mesothelioma but indicate that SRL172 was exerting an effect only as long as treatment was maintained. SRL172 did appear to be associated with small, non-statistically significant effects on survival time in adenocarcinoma patients.
      Quality of life measures showed an improvement in performance status (for example cognitive functioning and vitality), a reduction in treatment-related adverse effects (including nausea and vomiting and peripheral neuropathy) and relief of cancer-related symptoms (such as bodily pain and dyspnoea) in those additionally receiving SRL172, compared with the chemotherapy alone group (Tables 3 and 4). These improvements in quality of life in the terminal stages of NSCLC may be important giventhe many concerns regarding the administration of cancer chemotherapy in advanced disease including toxicity, the perceived high cost of treatment [
      • Goodwin P.J.
      • Shepherd F.A.
      Economic issues in lung cancer: a review.
      ], the low response rate and moderate impact on long-term survival [
      • Cullen M.H.
      • Billingham L.J.
      • Woodroffe C.M.
      • et al.
      Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life.
      ].
      Unfortunately, in this study only 30 patients (14%) received one or more SRL172 injections after the treatment phase. This is due to the high drop out in NSCLC studies due to early progressive disease of the order of 50% at 5 months, i.e. at the end of the15-week treatment phase. Sixty-three per cent of patients did not receive any further injections of SRL172 after the end of the 15-week treatment phase. It is possible that a greater effect of SRL172 might have been observed if a more intensive treatment schedule had been used particularly after the treatment phase. Results from a phase II study of SRL172 in renal cell cancer, in which patients did not receive any chemotherapy and continued with SRL172 throughout follow-up, suggested that monotherapy with SRL172 may offer a similar survival benefit to that conferred by established biological treatments in patients with renal cancer [
      • Patel P.M.
      • Johnston C.
      • Banks R.E.
      • et al.
      SRL172 (a killed Mycobacterium vaccae suspension) vaccination in the treatment of metastatic renal cell carcinoma.
      ].
      Safety assessments showed few differences between treatment groups. Although adverse effects were slightly higher with SRL172 and chemotherapy, this was not statistically significant and was likely to be due to increased reporting of the SRL172 plus chemotherapy arm in this non-blinded study. The combination of chemotherapy and SRL172 was well tolerated with mild injection site reactions occurring in 17% of SRL172 patients.
      The results from this study suggest that further work with patients in whom chemotherapy treatment is completed or not warranted, would be of interest and would require a placebo control to confirm the quality of life findings. Also, treatment should be given more frequently and/or continued for a longer period.

      Acknowledgements

      We are grateful to SR Pharma plc for their support. Participating institutions and investigators of the SR-ON-12 Study Group: The Royal Marsden Hospital, Surrey, UK and Mid-Kent Oncology Centre, Maidstone Hospital, Kent, UK (M. E. R. O’Brien); St Thomas’ Hospital, London, UK (P. Ellis); Royal Bournemouth Hospital, UK (T. Hickish); Wythenshawe Hospital, Manchester, UK (H. Anderson); Aberdeen Royal Infirmary, Scotland, UK(M. Nicolson); Nottingham City Hospital, UK (P. Woll); Leicester Royal Infirmary, UK (K. O’Byrne); St Mungo Institute, Glasgow Royal Infirmary, Scotland, UK (D. Dunlop); Yeovil District Hospital, Somerset, UK (S. Falk); Southampton General Hospital, UK (P. Johnson); Derriford Hospital, Plymouth, Devon, UK (M. Collinson); Weston Park Hospital, Sheffield, UK (M. Hatton); Addenbrooke’s Hospital, Cambridge, UK (D. Gilligan); Royal Surrey County Hospital, Guildford, UK (G. Middleton); ASKLEPIOS Fachklinik, Munchen Gauting, Germany (J. Von Pawel); Krankenhaus Grobhansdorf, Germany (M. Reck); Krankenhaus Zehlendorf, Berlin, Germany (R. Loddenkemper); Fachkrankenhaus für Lungenheilkunde u. Thoraxchiurgie, Berlin, Germany (K. Deperman); Allgemeines Krankenhaus, Hamburg, Germany (E. Kaukel); Krankenhaus der Elisabethanien, Linz, Austria (K. Aigner); Universitätskliniken Wien Innere Medizin I, Vienna, Austria (R. Pirker); Landeskrankenhaus Feldkirch, Bludesch, Austria (J. Rothmund); Regionalne Centrum Onkologii w Bydgoszczy, Bydgoszczy-Fordon, Poland (J. Tujakowski); Centrum Onkologii im. M. Sklodowskiej-Curie, Warsaw, Poland (M. Krzakowski); Wielkopolskie Centrum Chorob Pluc I Gruzlicy Oddzial Onkologii Pulmonologicznei Poznan, Poland (R. Ramlau); Centrum Onkologii w Krakowie, Kraków, Poland (M. Pawlicki); Mapi Values, Boston, MA, USA (B. Crawford); Department of Mathematics and Statistics, Boston University, USA (J. Massaro); GNB Limited, Chislehurst, Kent, UK (A. Cross); SR Pharma plc, London, UK (N. Tuckwell, D. Kennard, J. Povey).

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