Advanced lung disease (ALD) (FEV1pp<40%)
Initial phase 3 studies of CFTR modulators did not include pwCF with
advanced lung disease (ALD), defined as FEV1pp<40%. A Danish
single center observational study was performed in 21 pwCF with severe
lung disease ≥13 years old who were started on lum/iva as part of a
compassionate use program and followed for 12
months11. Criteria for inclusion were FEV1pp
< 30% for adults or FEV1pp <40% for children, or
demonstration of 2 criteria including FEV1pp <40% in adults
or <30% in children, FEV1pp slope less than -2.5% in past 12
months, chronic difficult to treat pulmonary infections, or BMI z-score
< -2.0 for children and BMI ≤ 18 for adults. The median slope
for FEV1pp decline was -2.6 in the year prior to treatment, compared to
-2.1 during the year of treatment. FEV1pp improved, with a mean change
of 3.1, 5.8, and 3.8%, at 1, 6, and 12 months, respectively.
Significant improvements in health-related quality of life and declines
in sweat chloride were seen, although increases in BMI and
cardiopulmonary exercise testing parameters did not reach significance.
In a case control study by Tong K et al , 72 F508del homozygous
subjects over age 12 years, with FEV1 <40%, from 7 Australian
CF centers were treated with lum/iva and followed for 12
months12. The control group included 33 subjects with
severe class 1/class 2 CFTR mutations ineligible for lum/iva, matched
for age, gender, and FEV1pp. The treatment group was found to have a
lower rate of PEx requiring IV antibiotic treatment, with a mean rate of
1.49 per year (standard deviation (SD) 1.74), compared to a mean rate of
3.06 (SD 2.42) per year in the control group. Those on lum/iva also had
prolonged time to first exacerbation, and increased rate of change in
FEV1pp (0.107/month versus -0.379/month in controls). However, as will
be reviewed below, there was a high rate of cessation of treatment of
32% over 12 months. These two studies suggested that lum/iva has
clinical benefit in pwCF with advanced lung disease.
Although the initial ETI studies excluded those with
FEV1pp<40%, there were a limited number of subjects (18 in
ETI group versus 16 in placebo group) whose FEV1pp decreased to that
level during the trial10. Those subjects on ETI did
have a mean increase in FEV1pp of 15.2% above placebo (95%CI 7.2 to
23.1%) without a significant change in the rate of AEs compared to
those with FEV1>40%10. Further
evaluation of patients with ALD was studied in a limited number of
subjects in an Irish real-world study using a managed access
program13. Fourteen adults with CF and FEV1pp
<40% received treatment with ETI. The time of pre ETI data
collection was variable and mean post-ETI follow up was 4.9±1.94 months.
ETI treatment led to improvement of mean FEV1pp from 27.3% at
approximately 30 days to 36.3% at approximately day 60
(p<0.0001). Additional outcomes included: improvement of mean
BMI from 20.7 kg/m2 to 22.3 kg/m2 (p<0.0001), and decrease in
mean sweat chloride from 104.9 mmol/l to 64 mmol/l (p<0.0001).
PEx rates decreased significantly (0.28 ± 0.17 exacerbations per month
in the 12 months prior to ETI, versus 0.04 ±0.07 exacerbations per month
during the follow-up period of 4.9 months (p<0.001)). ETI was
well tolerated, with hospitalization due to distal intestinal
obstructive syndrome (n=1) and kidney injury unrelated to study drug
(n=1), as the only significant AEs reported.
FEV1pp ≥90%
There has been a question as to whether pwCF with higher lung function
would have similar benefits from CFTR modulators compared to those with
lower lung function. A retrospective, observational study in the
Netherlands included patients over age 6 years with
FEV1pp≥90%14. Forty patients were followed before and
after lum/iva, for 12 months. Results revealed a stable FEV1pp
(-0.10%), an increase in BMI 0.88 kg/m2(p=0.001), and
decreased PEx rate from 1.03 to 0.53/person/year (p=0.003). CFQ-R scores
improved by only 2.8% overall (p=0.004), which is not considered
clinically significant, however, due to 22 out of 29 subjects improved
and only 7 out of 29 remained stable or deteriorated. Interestingly,
decline in sweat chloride occurred in all (mean difference of 27.3
mmol/L), but was more pronounced in patients under age 18 (mean
difference of 31.3 mmol/L).