Keywords
real-world data - anaplastic lymphoma kinase - non-small cell lung cancer
Introduction
Anaplastic lymphoma kinase (ALK) gene rearrangement is found in 1 to 7% of non-small
cell lung cancer (NSCLC) patients.[1]
[2]
[3] Its frequency is higher among nonsmokers, which may be as high as 17 to 20%.[1]
[4] Crizotinib is the first potent inhibitor of ALK tyrosine kinases and the first targeted
therapy approved for treating ALK-positive NSCLC.[5] Second-generation and third-generation ALK inhibitors (ALKi) like ceritinib, alectinib,
lorlatinib, and brigatinib are more efficacious and are better-tolerated agents.[6]
[7] Despite being superior to conventional chemotherapy, resistance does develop to
crizotinib, which can be treated with other agents.[8]
Till today, little real-world evidence is available from the developing countries
like India with varied genetic and ethnic backgrounds and a relatively higher prevalence
of the disease.
Because of the high cost, all the eligible ALK-mutated NSCLC patients do not get treated
with ALKi. Also, due to delays in the availability of molecular testing reports, many
patients in India receive chemotherapy before switching to ALKi maintenance, adding
to the diversified approach. The present multicenter study was therefore conducted
to evaluate the real-world experience related to the treatment patterns and clinical
and survival outcomes of patients with ALK-positive NSCLC. Network of Oncology Clinical
Trials India (NOCI) is a group of oncology centers supported by the Biotechnology
Industry Research Assistance Council (BIRAC) to develop a registry of cancers and
conduct collaborative clinical trials (www.noci-india.com). We collated data on patients with ALK-positive lung cancer from the six centers
of NOCI. An additional four centers from the state of Odisha contributed their data.
The combined data is presented in this article.
Methods
Collection of Data
Data of ALK rearrangement-positive NSCLC patients registered for treatment from 2014
to 2021 were collected retrospectively from the records maintained in each institution.
ALK rearrangement was diagnosed by immunohistochemistry, fluorescent in situ hybridization,
or next-generation sequencing.
Inclusion Criteria
Patients were eligible for enrolment if they had histologically confirmed locally
advanced, recurrent, or metastatic NSCLC that was positive for an ALK rearrangement
and received no previous systemic treatment for advanced disease, irrespective of
the brain metastasis.
Key Exclusion Criteria
Patients with incomplete records and those who were lost to follow-up were excluded
from the analysis.
The primary end point of the study was progression-free survival (PFS), whereas the
secondary end point was overall survival (OS). Each institution entered the data into
a predefined proforma common to all ten centers. The data elements captured were baseline
characters, type of testing for ALK, treatment details, use of ALKi and line of use,
the toxicity of ALKi, responses to treatment, and survival. The deidentified data
were collated and analyzed.
Statistical Analysis
The baseline characters were described as proportions and presented in groups. Four
groups were identified: those who received ALKi at the time of diagnosis of NSCLC,
those who started chemotherapy and then switched to ALKi after three to four cycles
(but before progression), those who received ALKi in later lines of treatment (after
progression with chemotherapy), and those who never received ALKi. The Kaplan–Meier
method estimated the median PFS and OS with 95% confidence intervals (CI). The log-rank
test was used to compare treatment groups at a 5% significance level (two-sided).
A stratified Cox proportional-hazards regression model was used to estimate the treatment
effect, expressed as a hazard ratio (HR) with a 95% CI. The study was approved by
the institutional ethics committee (vide IMS.SH/SOA/2021/097 letter dated 07.07.2021).
All procedures performed in studies involving human participants were in accordance
with the ethical standards of the institutional and/or national research committee
and with the 1964 Helsinki Declaration and its later amendments or comparable ethical
standards.
Results
Among the 67 patients who were diagnosed with ALK mutated lung cancer (males, n = 37; median age: 52 [26–80] years, 16 (24%) patients were smokers, and 12 (18%)
had brain metastasis at presentation. Forty-four (66%) patients received ALKi in the
first line. Of those, 22 (33%) patients were started on ALKi upfront, while 22 (33%)
started chemotherapy and switched to ALKi after a few cycles. Sixteen patients received
one to three cycles, and six patients got more than or equal to four cycles of chemotherapy
before switching to ALKi. The ALKis used were crizotinib (n = 28), alectinib (n = 6), and ceritinib (n = 10). Twenty-three (34%) patients received only chemotherapy in the first line ([Table 1], [Fig. 1]).
Table 1
Baseline characteristics of all patients with NSCLC who were ALK-positive
|
|
Front-line treatment
|
|
All patients
n = 67
|
Chemotherapy alone[c]
n = 23 (34.3%)
|
Chemotherapy followed by ALKi[b]
n = 22 (32.8%)
|
ALKi upfront
n = 22 (32.8%)
|
|
Median age (range)
|
52 (26–80)
|
55
|
55
|
50
|
|
Sex
|
|
|
|
|
|
Male
|
37 (55.2%)
|
10 (43.5%)
|
17 (77.3%)
|
10 (45.5%)
|
|
Female
|
30 (44.8%)
|
13 (56.5%)
|
5 (22.7%)
|
12 (54.5%)
|
|
ECOG PS
|
|
|
|
|
|
0-1
|
51 (76.1%)
|
18 (78.3%)
|
15 (68.2%)
|
18 (81.8%)
|
|
≥2
|
16 (23.9%)
|
5 (21.7%)
|
7 (31.8%)
|
4 (18.9%)
|
|
Smoking status
|
|
|
|
|
|
Never smoker
|
16 (23.9%)
|
3 (13.1%)
|
9 (40.9%)
|
4 (18.9%)
|
|
Nonsmoker
|
51 (76.1%)
|
20 (86.9%)
|
13 (59.1%)
|
18 (81.8%)
|
|
Stage at diagnosis
|
|
|
|
|
|
IIIb /IIIc
|
4 (6.0%)
|
2 (8.7%)
|
0 (0%)
|
2 (9.1%)
|
|
IV
|
63 (94.0%)
|
21 (91.3%)
|
22 (100%)
|
20 (90.9%)
|
|
Brain metastasis[a]
|
12 (17.9%)
|
3 (13.1%)
|
3 (13.6%)
|
6 (27.2%)
|
Abbreviations: ALKi, anaplastic lymphoma kinase inhibitor; ECOG-PS, Eastern Cooperative
Oncology Group Performance Status; NSCLC, non-small cell lung cancer.
a At presentation.
b ALKi started after three to four cycles of chemotherapy or at any point before progression
on first-line treatment.
c Out of the 23 patients who received chemotherapy alone in front-line, 10 patients
received ALKi as second-line treatment after progression, while 13 patients never
received ALKi.
Fig. 1 Patient disposition chart. ALKi, anaplastic lymphoma kinase inhibitor.
Response to Treatment
The objective response rate (ORR) (complete response [CR]+ partial response [PR])
at 6 months was superior for those who received ALKi in the front line compared to
those who received chemotherapy alone (64% [28/44] vs.26% [6/23], p = 0.02). Six patients receiving upfront ALKi achieved CR, while no patient receiving
front-line chemotherapy achieved CR. The responses were similar among those who started
with ALKi and those who received ALKi after a few cycles of chemotherapy. ORR was
similar among patients who received crizotinib, ceritinib, and alectinib (61% [17/28],
70% [7/10], and 67% [4/6], respectively, p = 0.508) ([Table 2]).
Table 2
Outcomes in various treatment groups
|
First-line chemo therapy
|
First-line ALKi
|
|
Overall response rate at 6 months
|
26%
|
63.6%
|
|
ALKi upfront
64%
|
Chemotherapy→ALKi maintenance
64%
|
|
Crizotinib
61%
|
Ceritinib
70%
|
Alectinib
67%
|
|
Median PFS with first-line treatment
|
9 months
|
19 months (p < 0.001, HR = 0.30, 95% CI: 0.17–0.54)
|
|
ALKi upfront
16 months
|
Chemotherapy→ALKi maintenance
22.0 months
|
|
Crizotinib
17 months
|
Ceritinib
19 months
|
Alectinib
22 months
|
|
Median overall survival
|
23 months[a]
|
34 months, (p = 0.19)
|
Abbreviations: ALKi, anaplastic lymphoma kinase inhibitor; CI, confidence interval;
HR, hazard ratio.
a Some ALKi in any lines versus no ALKi: 44 versus 14 months (p< 0.001, HR= 0.10, 95% CI 0.04–0.23).
Survival Outcomes
The median follow-up duration was 23 months (1–99 months). Fifty-four (81%) patients
received some ALKi in the first or subsequent lines, whereas 13 (19%) patients never
received any ALKis. Median PFS among those who received ALKi in front-line treatment
was superior to those who received chemotherapy alone (19 vs. 9 months; p < 0.001, HR = 0.30, [95% CI: 0.17–0.54]); [Fig. 2]). Among the ALKi, median PFS achieved with crizotinib, ceritinib, and alectinib
were similar (17, 19, and 22 months, respectively; p = 0.48). PFS did not differ between those who received ALKi as front-line treatment
or after a few cycles of chemotherapy (16 vs. 22 months; p = 0.24; [Table 2]). Patients who received more than or equal to 4 cycles of chemotherapy ALKi had
a median PFS of 23 versus 22 months (p = 0.41) for those who received one to three cycles of chemo before switching to ALKi.
The rate of progression in central nervous system was lower among those who received
ALKi (31 vs. 69%). In the second line, 21 patients received ALKi (crizotinib: 8, ceritinib:
8, alectinib: 3, lorlatinib: 2), and 28 received chemotherapy. Median PFS for ALKi
or chemotherapy in the second line was 14 and 5 months, respectively; p = 0.002. Among the ALKi, crizotinib, ceritinib, alectinib, and lorlatinib had median
PFS of 8, 24, 4, and 4 months, respectively; p = 0.77. In third line, six patients received ALKi (crizotinib: 1, ceritinib: 2, Alectinib:
3), and 12 patients received chemotherapy. Median PFS for ALKi and chemotherapy in
third line were 20 and 4 months, respectively; p = 0.009. One patient received ALKi (crizotinib: 1), and two patients received chemotherapy
in the fourth line. Median OS for those who received ALKi at any line of treatment
was superior to those who never received ALKi (44 vs. 14 months, respectively, p = 0.00, HR= 0.10, [95% CI: 0.04–0.23]) ;[Table 2], [Fig. 2]). Median OS for patients with or without brain metastasis at presentation was 20
versus 34 months, respectively; p = 0.01.
Fig. 2 Survival outcomes. ALKi, anaplastic lymphoma kinase inhibitor; OS, overall survival;
PFS, progression-free survival;
Toxicity
The commonest toxicities associated with crizotinib (across all lines) were gastrointestinal
(nausea and diarrhea) and were seen in 22/38 (58%) patients. Transaminitis was seen
in 12/38 (31.5%) patients, and two patients (5%) discontinued crizotinib because of
hepatotoxicity. Eight (out of 20) (40%) patients had gastrointestinal toxicities with
ceritinib, 7/20 (35%) had transaminitis, and 2/20 (10%) had sinus bradycardia and
QTc prolongation. One patient developed severe pneumonitis and discontinued ceritinib
because of the same. With alectinib, 3/12 (25%) had gastrointestinal toxicity, and
3/12 (25%) developed transaminitis. But none had discontinued alectinib or lorlatinib
because of toxicities.
Discussion
Our study is one of the few to report on the outcomes of ALK-positive lung cancers,
a rare entity constituting less than 5% of all patients with NSCLC.[9]
[10]
[11]
[12]
[13] The true incidence in India is unknown due to selective testing in most centers.
Despite their proven survival benefit, not all eligible ALK-mutated NSCLC patients
receive ALKi. Due to delays in the availability of molecular testing reports and the
time required to arrange to fund, many patients in India receive chemotherapy before
switching to ALKi maintenance. Despite these issues, our study clearly shows a significant
survival advantage for patients who received ALKi therapy at some point in their treatment
course. Nearly 60% of the patients in this series are from a government hospital where
patients hailed from low economic backgrounds. Almost 80% of patients could access
ALKi at some point in their treatment. The availability of support schemes has increased
access to these agents. Tumors with ALK fusion oncogenes or their variants are relatively
young, nonsmokers, and have adenocarcinoma histology.[12]
[14]
[15]
[16]
[17] A similar patient profile was seen in our study ([Tables 1] and [3]). In our study, five (7.4%) patients had signet ring cell histology, which may have
a higher prevalence among ALK-positive lung cancers.[18]
[19] Nearly one in five had brain metastasis at presentation. Response rate with first
line ALKi was 63.6% (crizotinib: 60.7% [17/28], ceritinib: 70% [7/10], alectinib:
66.6% [4/6], p = 0.508) and that with chemotherapy was 26.1%. These figures for ALKi are comparable
to those of studies like PROFILE 1014 and ASCEND-4.[20]
[21]
[22]
[23]
[24]
[25]
[26] But for patients treated with chemotherapy in first-line, response rates in our
study are much less numerically compared to the response rates of chemotherapy-treated
patients of the PROFILE 1014 trial (26.1 vs. 45%; [Table 3]). This difference may be attributed to the poorer performance status of the patients
in the real world compared to those typically enrolled in clinical trials. The ORR
for patients who were started on ALKi upfront was similar to those patients who were
switched to ALKi after a few chemotherapy cycles; (63.6% [14/22] for both groups).
But 18.2% (4/22) in the former group achieved CR, whereas only 9.1% (2/22) achieved
CR in the latter group. Though guidelines recommend starting upfront ALKi, this may
not be practicable in real-world settings. Delays are inevitable while waiting for
molecular testing results, ranging from 1 to 3 weeks in our centers. Even after knowing
that a patient is ALK mutated, time is required for them to arrange finances to procure
the drugs. However, there was no difference in PFS between patients receiving ALKi
upfront or those received after a few chemotherapy cycles. In the second and subsequent
lines of treatment, the PFS was superior with ALKi compared to chemotherapy. The median
OS for patients who received ALKi in any line of therapy was significantly longer
than for patients who never received ALKi (44 vs. 14 months). This is similar to data
from a multicenter study from India, which showed that a similar OS is achieved irrespective
of the line of ALKi used.[27] The study also highlights the strength of cooperative research networks like NOCI,
which helps in faster data acquisition and analysis in rarer cancer subsets similar
to our study. Limitations of the study include its retrospective nature, thus affecting
the quality of the real-world data. Also, under-reporting of adverse events cannot
be ruled out in low and middle-income countries like ours and results are to be interpreted
cautiously.
Table 3
Comparison of treatment outcomes for various ALK-positive metastatic lung cancer series
|
Our study
|
Shaw et al[23]
|
Noronha et al[28]
|
Patel et al[27]
|
|
Type of study
|
Real-world multicenter
|
Clinical trial
|
Real-world single center
|
Real-world multicenter
|
|
Number of patients
|
|
|
|
|
|
ALKi used
|
Crizotinib, ceritinib, alectinib, lorlatinib
|
Crizotinib
|
Crizotinib
|
Crizotinib, ceritinib
|
|
ORR to ALKi
|
63.6%
|
74%
|
53.6%
|
66%
|
|
ORR to chemotherapy
|
26.1%
|
45%
|
X
|
X
|
|
First-line PFS with ALKi
|
19 months
|
10.9 months
|
12 months
|
11.3 months
|
|
PFS with chemo followed by ALKi
|
22 months (1–3 cycles chemo) 23 months (≥4 cycles)
|
X
|
10 months
|
X
|
|
First-line PFS with chemo
|
9 months
|
7 months
|
X
|
X
|
|
OS with ALKi in any line
|
44 months (ALKi in any lines)
|
20.3 months (crizotinib followed by crossover to chemo)
|
Not reached
|
24.7 months (21.2 months for upfront ALKi, 26 months for switch maintenance with ALKi)
|
|
OS with chemo followed by ALKi in later lines
|
87 months
|
NR
|
39.8 months
|
38 months
|
|
OS with chemo
|
14 months
|
22.3 months (chemo followed by cross over to crizotinib)
|
X
|
X
|
Abbreviations: ALKi, anaplastic lymphoma kinase inhibitor; NR, not reached; ORR, objective
response rate; PFS, progression-free survival; OS, overall survival.
Conclusion
The use of ALKi in first line in ALK-positive metastatic NSCLC patients significantly
improved PFS compared to chemotherapy. The use of ALKi in subsequent lines resulted
in significantly prolonged OS in contrast to patients who never received ALKi. Efforts
must be undertaken to incorporate ALKi in the treatment of metastatic lung cancer
patients with ALK-EML4 rearrangement.
