Disposition of patients
Of the 133 patients included, 131 patients received at least one dose of naloxegol and were analyzed in the Safety population. Of the 124 patients who fulfilled all the selection criteria (Efficacy population), 86 patients (69.4%) completed the study at week 4. Early study termination was mainly due to patient death (n = 11), patient decision (n = 7), lost to follow-up (n = 11), or other reasons [n = 9; side effects (3), lack of efficacy (2), and disease progression (2)]. Among the 86 patients who completed the study, 79 were evaluable for the primary criterion (response to naloxegol based on data reported by the physicians).
Regarding patient self-reported questionnaires on constipation symptoms (PAC-SYM) and quality of life (PAC-QOL), 110 were analyzed at inclusion and 78 at W4. In addition, 69 patient diaries on naloxegol intake and bowel movements were analyzed. The response rate to naloxegol could be calculated in 62 of these 69 patients.
Patients’ baseline characteristics
Baseline characteristics of the patients of the Efficacy population are presented in Table 1. Patients frequently suffered from lung, breast or prostate cancer, with an advanced stage of the disease in the most cases, and two third of them were still treated by either chemotherapy or radiation therapy at inclusion. The median duration of opioid use at baseline was 9.0 weeks (interquartile range (IQR):2.4–29.1),
Table 1
Patient and disease characteristics at inclusion – Efficacy population (N = 124)
Baseline parameters | Number of analyzed patients | Efficacy Population N = 124 |
---|
Demographics | | |
Age (years), mean ± SD | 124 | 62.1 ± 12.1 |
Age < 70 years, n (%) | 124 | 95 (76.6%) |
Male sex, n (%) | 124 | 117 (63.2) |
Body mass index (kg/m²), mean ± SD | 114 | 23.8 (4.7) |
ECOG index, n (%) | 121 | |
≤ 2 | | 95 (78.5) |
> 2 | | 26 (21.5) |
Concomitant diseases, n (%) | 124 | 34 (27.4) |
Chronic kidney disease | | 8 (6.5) |
Diabetes | | 6 (4.8) |
Hypertension | | 5 (4.0) |
Main cancer locations, n (%) | 124 | |
Lung | | 22 (17,7) |
Breast | | 20 (16,1) |
Prostate | | 13 (10,5) |
Ear, nose & throat | | 11 (8,9) |
Digestive tract | | 11 (8,9) |
Kidney | | 8 (6,5) |
Bladder | | 7 (5,6) |
Metastases at inclusion, n (%) | 100 solid tumors | 80 (80.0) |
Bones | | 56 (56.0) |
Liver | | 26 (26.0) |
Lung | | 25 (25.0) |
Nodes | | 15 (15.0) |
Current treatment of cancer, n (%) | 124 | 103 (83.1) |
Chemotherapy | | 67 (54.0) |
Radiation therapy | | 19 (15.3) |
Immunotherapy | | 16 (12.9) |
Hormonal therapy | | 11 (8.9) |
Targeted therapy | | 11 (8.9) |
Total score of the PAC-SYM at inclusion, mean ± SD | 107 | 2.2 ± 1.2 |
Total score of the BFI at inclusion, mean ± SD | 118 | 71.2 ± 19.6 |
Total score of the PAC-QOL at inclusion, mean ± SD | 104 | 2.1 ± 0.6 |
BFI, Bowel Functional Index; ECOG, Eastern Cooperative Oncology Group; Patient Assessment of Constipation Quality of Life; PAC-SYM, Patient Assessment of Constipation Symptoms; SD, standard deviation |
Ongoing opioids were oxycodone (54.8% of patients), morphine (33.9%), fentanyl (29.0%), tramadol (7.3%), opium (2.4%), codeine (1.6%), and methadone (0.8%), with a median dosage of 60 mg (IQR: 22.5–105.0) of oral morphine equivalent at inclusion.
Other treatments that could lead to constipation were also taken at inclusion by 83.5% of patients (grade 1 analgesic: 74.4%, anxiolytic: 33.1%, antidepressant: 27.3%, steroid: 22.3%, anticonvulsant: 18.2%, antispasmodic: 9.1%, anticholinergic: 5.8%).
Prior to inclusion, the median duration of treatment with laxatives was 32.5 days (IQR: 11.0-112.0). At inclusion, patients received osmotically acting laxatives (93.5%), enemas (9.7%), and/or bulk forming laxatives (5.6%). Over the last 7 days prior to inclusion, patients had a mean number of 2.1 ± 1.9 bowel movements.
At inclusion, the median duration of OIC was 4.9 weeks (IQR: 1.6–10.9). The naloxegol starting dose was 25 mg/day in 78.2% of patients, and this dose was used in 82.0% of patients (n = 91) at W4. Over the study period, 76.2% of the patients (n = 64) received at least one concomitant laxative (osmotic-type laxatives in 67.9% of the cases).
In the overall Efficacy population, no differences were observed at inclusion between evaluable (n = 79) and not evaluable (n = 45) patients according to the BFI score (p = 0.922) and the PAC-SYM score (p = 0.560).
Effectiveness
The response to treatment at W4 (primary criterion) was reached by most of the 79 evaluable patients in the Efficacy population (73.4%, 95% CI [63.7%-83.2%]), irrespective of the use of laxatives during patient follow-up (76.7% [66.0%-87.4%] and 63.2% [41.5%-84.8%], respectively with and without laxatives) (Fig. 1). Univariate analysis (Table 2) highlighted that the response to naloxegol was associated (p ≤ 0.2) with the following baseline parameters: metastatic cancer, bone metastasis, duration of opioid treatment prior to inclusion, duration of OIC prior to inclusion, number of weekly stools, abdominal symptoms using the PAC-SYM subscale, concomitant analgesics, anxiolytics, antispasmodics, and starting dose of naloxegol. Based on these ten parameters, multivariate analysis (Table 2) showed two baseline parameters were independent predictive factors of treatment response (p < 0.05): duration of OIC less than the median value of 9 weeks (p = 0.006), and bone metastasis (p = 0.047).
Table 2
Factors associated with naloxegol response
Baseline parameters | Univariatea OR [95% CI] p value | Multivariatea OR [95% CI] p value |
---|
Metastatic stage of the cancer | 2.31 [0.67–8.01] | |
| 0.1861 | |
Bone metastasis | 2.99 [0.97–9.23] | 3.62 [1.02–12.82] |
| 0.0574 | 0.0473 |
Duration of opioids < 9 weeks (median) | 5.14 [1.63–16.18] | 5.16 [1.59–16.77] |
| 0.0051 | 0.0063 |
Duration of OIC < 1.12 month (median) | 3.14 [1.02–9.66] | |
| 0.0455 | |
Mean number of tools over the last 7 days | 0.71 [0.50–1.01] | |
| 0.0584 | |
Abdominal symptoms (mean PAC-SYM subscore) | 0.59 [0.33–1.07] | |
| 0.0808 | |
Concomitant analgesics | 3.39 [1.16–9.90] | |
| 0.0259 | |
Concomitant anxiolytics | 3.78 [0.99–14.44] | |
| 0.0520 | |
Concomitant antispasmodics | 0.22 [0.03–1.44] | |
| 0.1143 | |
Start dose of naloxegol at 12.5 mg | 0.38 [0.13–1.14] | |
| 0.0845 | |
CI, Confidence Interval; OR, Odds Ratio; PAC-SYM, Patient Assessment of Constipation Symptoms |
aThe factors significant at the 20% level are presented for univariate analysis and entered the final model; factors significant at the 5% level are presented for multivariate analysis |
On the basis of the data from the 62 patients who completed assessable diaries during the 4-week study period, the response rate (with or without laxatives during follow-up) was close to the estimate based on data reported by physicians: 69.4%, 95% CI [57.9% – 80.8%].
Based on diaries completed by patients between inclusion and W4, the mean number of their weekly bowel movements increased from 2.1 ± 1.9 at inclusion to 3.9 ± 2.1 at week 4. A total of 68.7% of patients had a first stool the same day or the day after the first intake of naloxegol. Regarding the other symptoms of constipation, the mean total scores of the 0–4 scale of the PAC-SYM and the 0-100 scale of the BFI decreased (i.e. improved) under treatment, from 2.1 ± 0.7 to 1.3 ± 0.8 (Fig. 2A), and from 70.9 ± 19.2 to 40.0 ± 26.0 (Fig. 2B), respectively, in patients assessable at both visits (inclusion and W4). The strongest improvements were observed for the subscale ‘Stool symptoms of the PAC-SYM (from 2.6 ± 0.8 to 1.5 ± 0.9), and the subscale ‘Personal judgement of constipation’ of the BFI (from 77.0 ± 23.2 to 37.2 ± 28.8). The majority of patients had a clinically relevant change in constipation during follow-up: 70.7% (95% CI [60.4%-81.0%]) based on the PAC-SYM, and 73.4% (95% CI 63.7%-83.2%]) based on the BFI.
The quality of life of patients improved at W4, with a decrease in PAC-QOL score from 2.2 ± 0.6 to 1.5 ± 0.7 (Fig. 3). Overall, 62.9% of patients (95% CI [51.5%-74.2%]) had a clinically relevant change in quality of life.
Satisfaction with naloxegol treatment
For the analyzed patients, the majority of the physicians and patients themselves were satisfied with the naloxegol treatment at W4: a rating ≥ 5 was observed in 81.4% and 72.4% of the cases, respectively, using a 1–10 numerical scale.
Safety
At least one adverse event (AE) was reported in 43 patients (32.8%) during the study (median follow-up of patients: 4.3 months; range: 0.3–14.9), including 21 patients (16.0%) with at least one serious AE (SAE). Among the 15 AEs related to naloxegol according to investigators (11 patients, 8.4%), the most common events were gastrointestinal disorders (12 events reported in 9 patients, 6.9%) (Table 3). Among these 12 gastrointestinal AEs, 6 diarrheas were reported in 5 patients (3.8%), all of them having started naloxegol at the dose of 25 mg. One non-serious withdrawal syndrome was reported. Only one related SAE was reported (diarrhea, 0.8% of patients).
Table 3
Adverse events related to naloxegol - Safety population (N = 131)
| Starting dose of naloxegol | Total N = 131 |
---|
n (%) | 25 mg N = 102 | 12.5 mg N = 29 |
---|
At least one related adverse event | | 9 (8.8) | 2 (6.9) | 11 (8.4) |
Gastrointestinal disorders | All | 7 (6.9) | 2 (6.9) | 9 (6.9) |
Diarrhea | 5 (4.9) | - | 5 (3.8) |
Abdominal pain | 1 (1.0) | 1 (3.4) | 2 (1.5) |
Constipation | - | 1 (3.4) | 1 (0.8) |
Nausea | 1 (1.0) | - | 1 (0.8) |
Vomiting | 1 (1.0) | - | 1 (0.8) |
Eructation | - | 1 (3.4) | 1 (0.8) |
General disorders and administration | All | 2 (2.0) | - | 2 (1.5) |
Pain | 1 (1.0) | - | 1 (0.8) |
Withdrawal syndrome | 1 (1.0) | - | 1 (0.8) |
Metabolism and nutrition disorders | All | 1 (1.0) | - | 1 (0.8) |
Decreased appetite | 1 (1.0) | - | 1 (0.8) |
Thirty AEs experienced by 22 patients (16.8%) led to naloxegol discontinuation during the study, mainly as cancer progression (8 events, 6.1% of patients) and diarrhea (4 events, 3.1% patients, all of them in the 25-mg group).
Thirteen deaths were associated with AEs, without causal relationship with naloxegol as assessed by physicians.