Keywords
alectinib - ALK - anaplastic lymphoma kinase - LMIC - low- and middle-income countries - OS - overall survival - PFS - progression-free survival
Introduction
Lung cancer is one the most common malignancies in the world and India with high mortality rate among all other cancers.[1]
[2] Molecular profiling and targeted therapy has improved outcome of ALK rearranged lung cancer patients.[3] After epidermal growth factor receptor mutation, the second most frequent mutation is ALK kinase domain rearrangement, which is detected by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or next-generation sequencing (NGS) techniques in 3 to 5%.[4] The clinical presentation making ALK-positive patients different from other nonsmall cell lung carcinoma was younger age, female sex predominance, never or light smokers, and a greater propensity for brain metastases.[5] First-generation ALK-directed tyrosine kinase inhibitor (TKI) crizotinib has shown superior disease control and survival outcome as well as better tolerance and safety as compared with chemotherapy.[6] Similarly, second-generation drugs ceritinib and alectinib are better against crizotinib.[7] Alectinib having additional advantage over crizotinib and ceritinib for better central nervous system (CNS) disease control due to better blood–brain barrier penetration.[8] However, data are scant from real-world settings especially from low- and middle-income countries (LMICs) like India. This study presents an audit of the safety and efficacy of patients receiving alectinib in the first-line for ALK rearrangement-positive advanced metastatic lung cancer, which is the first largest data from India.
Methods
This is a single-center, retrospective study of patients who received alectinib from January 2018 to March 2022. Data censoring was done on August 10, 2022. The data were entered in Excel sheet and included the baseline demographic data, diagnosis, comorbidity, method of molecular testing, treatment details, clinical and radiological response, date of disease progression, date of death, and toxicity details. Response assessment was performed using computed tomography (CT) scan of the thorax, abdomen, and if needed pelvis. For those cases where baseline positron emission tomography (PET)-CT was performed, repeat PET-CT was done for response assessment. Brain magnetic resonance imaging scan was performed for all cases at baseline and then a follow-up scan was done only if clinically indicated as per our institution protocol. Responses were classified according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Response assessment was done every 3 months after the commencement of treatment or at any symptoms/signs of clinical progression whichever was earlier. Adverse events during treatment were documented and graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.02. The baseline workup prior to start of therapy included complete blood counts, serum electrolytes, liver and renal function tests, electrocardiogram, and echocardiogram.
Inclusion and Exclusion Criteria
All patients with metastatic nonsmall cell lung cancer with ALK rearrangement positive with either IHC or FISH or NGS were included who received alectinib as first-line therapy. Also, those patients who were started initially with chemotherapy and later switched to alectinib after one or two cycles with the confirmation of ALK rearrangement was considered as first-line therapy and included in this analysis. It is common practice to start a patient on systemic chemotherapy at presentation due to symptomatic disease and switch to targeted therapy after confirmation of mutation.
Adverse Events
At the start of therapy, patients were counseled for the possible toxicities by the treating physician. Patients were subsequently followed up in the outpatient department 1 week post-start of therapy followed by either a monthly or three monthly basis depending on the convenience of the patients, as most of the patients came to our center from other states. For any complications, the patients were followed up in the emergency department.
Statistics
The survival endpoints were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time (in months) from the start of alectinib to radiological progression or death due to any cause if it happened before disease progression or the last follow-up date whichever was earlier. Progression was defined as clinical and radiological progression as per RECIST v 1.1 or death due to any cause. OS was the time in months from the date of diagnosis until death from any cause or date of last follow-up.
The qualitative data were analyzed with the Pearson's chi-square test, Fisher's exact test, or Mann–Whitney test. Kaplan–Meier analysis was done to calculate PFS and OS. All the data were analyzed with SPSS version 23 (IBM Corp., New York, United States).
Data Accessibility Statement
We state that all the datasheets will be made available to the reviewing journal on request.
Ethics Statement
The lung cancer audit is an institutional ethics committee-approved observational protocol and is registered with the Clinical Trials Registry India (registration number: CTRI/2013/01/003335).
Since this study is a retrospective audit of patients treated with standard institutional protocol, ethical clearance was not sought.
Results
Baseline Characteristics
A total of 50 patients received alectinib in first line from January 2018 to March 2022. A total of 441 patients were diagnosed in the same period. Out of these, 11.3% received tab alectinib in first line. At the time of analysis the median follow-up was 18 months (13.1–22.8 months). [Table 1] shows the baseline characteristics of the patients. The median age was 52.5 years (range: 28–81 years); out of which 42% were less than or equal to 50 years of age, 30% between 51 and 60 years of age, and 28% were more than 60 years of age. Fifty-four percent were male and 46% were female. Only 10% of patients had a smoking history. Seventy percent of patients were of Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) 0 or 1. Only 24% were ECOG-PS 2 and 6% were ECOG-PS 3 or 4 at the time of the start of alectinib. A total of 15 patients out of the total 50 patients presented with brain metastasis, of which 10 patients had symptomatic disease and hence after consultation with radiation oncologist were planned for radiation therapy. All these 10 patients received whole-brain radiation therapy (WBRT). WBRT was started before any systemic therapy. Note that 52% (n = 26) patients had bone metastasis and only one-third of them received bone-modifying agent (all except one received zoledronic acid and one received denosumab). Other sites of metastasis in decreasing sequence were 42% pleura, 28% lung, adrenal 12%, pericardium and muscle 6% each, and only 2% had leptomeningeal disease before starting alectinib at the time of presentation. Method for ALK testing included IHC 92%, FISH 2%, and NGS 6%.
Table 1
Baseline characteristics
|
Characteristics (total, n = 50)
|
Numbers (n)
|
Percentage (%)
|
|
Age (median = 52 y)
|
|
|
|
Less than 50 y
51–60 y
61 y and more
|
21
15
14
|
42
30
28
|
|
Sex
|
|
|
|
Male
Female
|
27
23
|
54
26
|
|
Smoking
|
|
|
|
Yes
No
|
5
45
|
10
90
|
|
ECOG Performance Status (PS)
|
|
|
|
PS 0 or 1
PS 2
PS 3 or 4
|
35
12
3
|
70
24
6
|
|
Sites of metastasis
|
|
|
|
Bone
Pleura
Brain
Lung
Adrenal
Pericardium
Muscle
leptomeningeal
|
26
21
15
14
6
3
3
1
|
52
42
30
28
12
6
6
2
|
Abbreviation: ECOG, Eastern Cooperative Oncology Group.
Table 2
Response
|
Type of response (total, n = 50)
|
Numbers
|
Percentage
|
|
Complete response
|
1
|
2
|
|
Partial response
|
37
|
74
|
|
Stable disease
|
8
|
16
|
|
Progressive disease
|
4
|
8
|
Fig. 1 Response to Alectinib.
Among 50 patients who were treated with the first-line alectinib, 74% showed partial response and 2% showed complete response, that is, overall 76% showed clinical response to therapy. Stable disease was seen in 16% patients. Disease progression was seen in 8% of the patients only.
Table 3
Survival
|
Event
|
Median (mo)
|
Expected 3 years (%)
|
|
PFS
|
Not reached
|
69.3
|
|
OS
|
Not reached
|
85.7
|
Abbreviations: OS, overall survival; PFS, progression-free survival.
Fig. 2 Progression-free survival.
Fig. 3 Overall survival.
Median PFS and median OS were not reached, with expected 3-year PFS and OS rates 85.7 and 69.3%, respectively ([Figs. 2] and [3]).
Progression ([Table 4])
Table 4
Progression
|
Progression
|
Number (n)
|
Percentage (%)
|
|
Yes
No
|
11
39
|
22
78
|
|
Subsequent therapy received (among 11 patients)
Yes
Lorlatinib
Chemotherapy
|
10
7
3
|
91
64
27
|
Only 22% (n = 11) patients had progressive disease till now, out which 91% (10) received subsequent therapy; majority received lorlatinib 64% (n = 7) and 27% (n = 3) patients received chemotherapy as subsequent therapy on progression after alectinib. One patient defaulted for subsequent therapy. Only 8% (n = 4) patients expired during the study period. The most common sites of progression were the pleura (10%) and liver (6%). Two percent each had progression in the brain, adrenal, lung, and supraclavicular lymph node.
Adverse Events ([Table 5])
Table 5
Adverse events
|
Event
|
Grade 1 or 2 (%)
|
Grade 3 or 4(%)
|
|
Anemia
|
36
|
4
|
|
Hyperbilirubinemia
|
8
|
−
|
|
Dry skin
|
6
|
−
|
|
Dyspepsia
|
6
|
−
|
|
Transaminitis
|
6
|
−
|
|
Constipation
|
2
|
−
|
|
Diarrhea
|
2
|
−
|
|
Myalgia
|
2
|
−
|
|
Fatigue
|
2
|
−
|
|
Anorexia
|
2
|
−
|
|
Dysgeusia
|
2
|
−
|
The most common adverse effect was anemia seen in 40% of the patients, but majority were grade 1 or 2, only 4% had grade 3 anemia. Next was asymptomatic hyperbilirubinemia 8%, all were grade 1 or 2 and direct type. Dry skin and dyspepsia were seen in 6%. Dyslipidemia and uncontrolled sugar were seen in 6% each. Transaminitis was also seen in 6% of the patients. Uncommon side effects, which were seen one patient each (2%), were constipation, diarrhea, myalgia, fatigue, anorexia, and dysgeusia. None of these were grade 3 or more. No interruption or dose modification of the therapy was needed in any patient because of the adverse events.
Discussion
Multiple anti-ALK agents are approved in the first line. The first-generation ALK-TKI crizotinib and another second-generation ALK-TKI ceritinib are approved in first line for metastatic ALK-rearrangement positive metastatic lung cancer patients. Both these drugs are commonly used in LMICs at present due to financial reasons. But patient on these drugs progresses in a year or two.[9]
[10] Common reason for this is the development of resistance mutation in the ALK-kinase domain. Another common reason is CNS progression due to poor blood–brain barrier penetration of these drugs. Advantage of alectinib in first line is its broader action over these resistance mechanisms in the ALK-kinase domain and higher CNS penetration that leads to better intracranial response and lesser CNS progression over the course of the treatment. Because of effective CNS penetrant activity of Alectinib brain radiation avoided in these patients who are expected to have multiple of years of life ahead and can have socially productive life.
Our study shows that patients with these ALK-rearrangement positive metastatic lung cancer are commonly younger (72% are less than 60 years and only 28% were above 60 years of age). This is similar to other histological data.[11] Again, similar to the histological demographic profile our patients were also commonly nonsmoker (90%) and had aggressive disease at presentation (52% bone, 42% pleura, 30% CNS, 28% bilateral lung metastatic disease).[11] Approximately half of the patients were female (46%), again showing the incidence rate is higher in females.[11]
In our data, objective response rate was 76% (including 2% complete response (CR) rate), this is approximately similar to the response rate seen in the ALEX trial, 83% (including 4% CR rates), meaning in real world also this drug is very efficacious irrespective of the population.[12] Only 2% patients showed CNS progression on alectinib treatment course in our data, which is much better as opposed to crizotinib and ceritinib where one-third to one-half of the patients develop CNS progression.[13]
[14] In the ALEX trial, 12% patients had CNS progression versus 45% patients with crizotinib.[12]
[13] So, our data also show good intracranial effect of this drug. Another important point noted in our study was bone-modifying agent not required in the majority of the patients (among 52% patients with bone metastatic disease only 14% received bone-modifying therapy) and they had good bone disease control; in fact, none of the patients has shown progression in bone disease or any skeletal event who had progressive disease.
In our study, the median PFS and median OS were not reached. This is expected as the present median follow-up was 18 months. In the ALEX trial,[12] the median PFS was 35 months and the median OS was not reached till the latest update of the ALEX trail, so more follow-up is needed to reach the median PFS and median OS of our patients. In our data, the expected 3-year PFS rate is 69.3% and OS rate is 85.7%. The 5-year OS rate in the ALEX trial was 62% with alectinib and 45% with crizotinib.[12] So, our data also look promising in terms of expected long-term survival of our population. Again, when we look into survival, alectinib showed similar promise in real world as it did in trial population.
In our study, the adverse event rate was low except for anemia seen in 40% patients, but majority had grade 1 or 2 anemia. Only 4% had grade 3 anemia. Other adverse events seen were transaminitis, hyperbilirubinemia, bowel abnormality, fatigue, dysgeusia, and skin dryness, but incidence rates were in single digit and none were grade 3 or 4 adverse events. So, there was no drug interruption or dose modification needed in any patient. As against the ALEX trial,[12] the types of adverse events were similar, with anemia being the common adverse event. But the ALEX trial has shown 41% rate of grade 3 or 4 adverse events with alectinib and 50% rate of grade 3 or 4 adverse events with crizotinib as opposed to 4% in our study, which is an odd finding in our study and may be due to the retrospective nature of our study. In the ALEX trial, drug interruption, dose modification, and discontinuation were seen in 16, 19, and 11%, respectively, with alectinib and 21, 25, and 13% with crizotinib, respectively, but none in our study. So, in the real-world setting it gives assurance that alectinib is as safe as it is in trial population.
The major limitation of the study is its retrospective nature with its inherent errors, but our data has not shown any odd or different alarming finding. So, from a country like India this largest data gives reassurance regarding the safety and efficacy of alectinib in real-world scenario.
Conclusion
This real-world data from LMIC like India shows the durable effectiveness of alectinib in first-line therapy in ALK-rearranged metastatic lung cancer is similar to trial population without any new alarming sign related to safety and tolerability.
