Abstract
Introduction
Patients with advanced ALK-positive non-small cell lung cancer (NSCLC) typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation (cCRT).
Methods
We conducted a retrospective study using a multi-center study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015-2022 were included. Patients received ALK TKI, durvalumab, or observation after cCRT. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAE) were classified by Common Terminology Criteria for Adverse Events v5.0. Outcomes were assessed by multivariable Cox regression analysis.
Results
Sixty-seven patients were included, of whom 39 (58%) were female. Median age was 57 years (IQR: 49-67). Fifteen received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the 3 groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached [NR], 95% CI 22.7-NR) versus durvalumab (11.3 months, 95% CI 8.9-18.5, hazard ratio [HR]=0.12, 95% CI: 0.026-0.5, p-adjusted=0.006) or observation (7.2 months, 95% CI 3.4-10.6, HR=0.04, 95% CI: 0.009-0.2, p-adjusted<0.0001). Durvalumab significantly improved median rwPFS compared to observation (HR=0.37, 95% CI: 0.19-0.71, p-adj = 0.002, p-adjusted=0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared to patients on observation (ALK TKI-observation: p=0.04; durvalumab-observation: p=0.03). TrAE of any grade occurred in 8 (53%) and 11 (37%) patients treated with ALK-TKI and durvalumab, respectively. Grade ≥3 trAEs occurred in 27% (n=4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab.
Conclusions
Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes seen with either durvalumab or observation. While both ALK TKI therapy and durvalumab offer an extension in OS compared to observation alone, it appears that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient.
Introduction
In unresectable stage III NSCLC, guidelines recommend concurrent chemoradiation (cCRT), followed by consolidation durvalumab, based on the PACIFIC trial, regardless of mutational status(1, 2). However, the benefit of durvalumab has been questioned in patients with EGFR-mutant and ALK-positive tumors(3, 4).
In addition to the established benefit of tyrosine kinase inhibitors (TKIs) in advanced NSCLC, recent studies highlight the advantages of targeted therapies at earlier stages of cancer. In unresectable stage III EGFR-mutant NSCLC, consolidation osimertinib has been associated with significantly longer real-world progression-free survival (rwPFS) and central nervous system (CNS) rwPFS, outperforming both durvalumab and observation(3, 5). Similarly, the ALINA trial showed adjuvant alectinib significantly improved disease-free survival compared to chemotherapy in patients with resected ALK-positive NSCLC(6). This study compares the clinical outcomes and safety profiles of consolidation ALK TKI versus durvalumab or observation in stage III unresectable ALK-positive NSCLC.
Materials and Methods
Study Population
De-identified data from 17 institutions were obtained (Table S1). Medical charts were manually reviewed from each participating institution. Inclusion criteria were: 1) patients with unresectable stage IIIA-C NSCLC (per AJCC 8th edition); 2) tumors harboring ALK-fusions detected by clinically-approved testing platforms including immunohistochemistry, fluorescence in situ hybridization, or next-generation sequencing; 3) treatment with ≥two cycles of platinum-based chemotherapy concurrently with radiation therapy between 1/1/2015 and 12/31/2022. Patients treated with sequential CRT were excluded.
Patients were divided into three cohorts according to the consolidation strategy: 1) ALK TKI, 2) durvalumab, or 3) observation. Initial time of retrospective study entry was determined to be the date of initiation of cCRT. This study was approved by the Institutional Review Boards (IRB) at participating institutions (Supplementary material).
Endpoints
The co-primary endpoints were rwPFS and overall survival (OS) (Supplementary material). Secondary endpoints were: (1) treatment-related adverse events (trAEs) during consolidation, graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and (2) intracranial rwPFS (rwicPFS), defined as the time from cCRT initiation to symptomatic CNS recurrence.
Statistical Analyses
Descriptive statistics were used to summarize patient characteristics. OS, rwPFS, and rwicPFS were estimated using the Kaplan-Meier method and log-rank tests were performed to compare sub-cohorts. Multivariable Cox proportional hazards regression models for rwPFS and OS were performed and adjusted for variables selected a priori: stage (IIIA, IIIB, IIIC), age, and nodal status. Adjusted p-values were reported. Statistical analyses were performed using R 4.3.2.
Results
Of 67 patients with unresectable stage III ALK-positive NSCLC, 15 (22%) received consolidation ALK TKIs, 30 (45%) durvalumab, and 22 (33%) observation (Figure S1, Table 1). Median follow-up time per cohort was 15.7 months (95% CI: 7.1-51.1) for ALK TKI, 44.2 months for durvalumab (95% CI: 38.7-50.7), and 64.8 months for observation (95% CI: 25.6-95.3). Median age at CRT initiation was 50 years for ALK TKI-treated patients (Q1-Q3: 49-83), 57 years for durvalumab-treated patients (Q1-Q3: 50-65), and 60 years for patients observed (Q1-Q3:49-67). Within the ALK TKI cohort, 10 patients were treated with alectinib, 3 with crizotinib, and 1 each with lorlatinib and brigatinib. Consolidation ALK TKIs and durvalumab were initiated at a median of 45 days (Q1-Q3: 27-60) and 41 days (Q1-Q3: 35-60) after completion of concurrent chemotherapy, respectively. Median time on ALK TKIs was 24.7 months (95% CI: 10.8-not reached [NR]) versus 6.5 months (95% CI: 5.1-9.4) on durvalumab (p<0.0001).
Table 1.
Baseline characteristics of patients undergoing treatment with consolidation therapy or observation
| Total (N=67) |
ALK TKI (N=15) |
Durvalumab (N=30) |
Observation (N=22) |
P-value | |
|---|---|---|---|---|---|
| Age – Median (IQR) | 50 [49-83] | 57 [50-65] | 60 [49-67] | 0.9 | |
| Sex | |||||
| Female | 39 (58%) | 11 (73%) | 17 (57%) | 11 (50%) | 0.4 |
| Male | 28 (42%) | 4 (27%) | 13 (43%) | 11 (50%) | |
| Race | 0.03 | ||||
| White | 39 (63%) | 6 (40%) | 20 (71%) | 13 (68%) | |
| Asian | 19 (31%) | 6 (40%) | 8 (29%) | 5 (26%) | |
| Black | 1 (1.6%) | 0 (0.0%) | 0 (0.0%) | 1 (5.3%) | |
| Other | 3 (4.8%) | 3 (20%) | 0 (0.0%) | 0 (0.0%) | |
| Not Reported | 5 | 0 | 2 | 3 | |
| Smoking | 1 | ||||
| Former/Current | 26 (39%) | 6 (40%) | 12 (40%) | 8 (36%) | |
| Never | 41 (61%) | 9 (60%) | 18 (60%) | 14 (64%) | |
| PD-L1 TPS * | 0.6 | ||||
| <1% | 13 (27%) | 4 (31%) | 5 (21%) | 4 (36%) | |
| ≥1% | 35 (73) | 9 (69%) | 19 (79%) | 7 (64%) | |
| Not Reported | 19 | 2 | 6 | 11 | |
| Stage | 0.3 | ||||
| IIIA | 18 (27%) | 2 (13%) | 7 (23%) | 9 (41%) | |
| IIIB | 39 (58%) | 11 (73%) | 17 (57%) | 11 (50%) | |
| IIIC | 10 (15%) | 2 (13%) | 6 (20%) | 2 (9.1) | |
| Nodal status | 0.4 | ||||
| N1 | 1 (1.5%) | 0 (0.0%) | 0 (0.0%) | 1 (5%) | |
| N2 | 26 (40%) | 6 (40%) | 10 (33%) | 10 (50%) | |
| N3 | 38 (59%) | 9 (60%) | 20 (67%) | 9 (45%) | |
| Not Reported | 2 | 0 | 0 | 2 | |
| ECOG PS Status | 0.6 | ||||
| 0 | 24 (39%) | 6 (40%) | 13 (46%) | 5 (26%) | |
| 1 | 36 (58%) | 9 (60%) | 14 (50%) | 13 (68%) | |
| 2 | 2 (3.2%) | 0 (0.0%) | 1 (3.6%) | 1 (5.3%) | |
| Not reported | 5 | 0 | 2 | 3 | |
| ALK Fusion Partner | 1 | ||||
| EML4 | 34 (92%) | 10 (91%) | 13 (93%) | 11 (92%) | |
| Uncommon Partners * | 3 (8.2%) | 1 (9.1%) | 1 (7.1%) | 1 (8.3%) | |
| Not reported | 30 | 4 | 16 | 10 | |
| ALK fusion determination | 0.014 | ||||
| FISH | 6 (9%) | 4 (27%) | 2 (6.7%) | 0 (0%) | |
| IHC | 18 (27%) | 1 (6.7%) | 7 (23%) | 10 (45%) | |
| NGS | 43 (64%) | 10 (67%) | 21 (70%) | 12 (55%) |
Include MEMO1, KIF5B, and HIP1
Six (40%) patients treated with ALK TKIs discontinued treatment, two due to disease progression and four due to toxicity (Figure S2). Among patients treated with durvalumab, eight (27%) completed 1-year treatment and twenty patients discontinued treatment due to either disease progression (n=17, 57%) or toxicity (n=3, 10%). Of forty-eight (72%) patients who received a subsequent systemic therapy, 4 (27%) were in the ALK TKI cohort, 24 (80%) in the durvalumab cohort, and 20 (91%) in the observation cohort, of which the majority (96%) received ALK TKI.
Survival Outcomes
rwPFS
For the durvalumab and observation cohorts, most progression events occurred within the first year after cCRT (durvalumab:17/25; observation:17/22). Adjusting for nodal status, status and age, the median rwPFS was not reached (95%CI:22.7-NR) in the ALK TKI cohort, was 11.3 months (95% CI:8.9-18.5) in the durvalumab cohort, and 7.2 months in the observation cohort (95% CI: 3.4-10.6 (Figure 1A); HR-adjALK TKI-durvalumab = 0.12 [95% CI: 0.026-0.5], p-adj=0.006; HR-adjALK TKI-observation = 0.04 [95% CI: 0.009-0.2], p-adj= 0.00004; HR-adjdurvalumab-observation = 0.37 [95% CI: 0.19-0.71, p-adj = 0.002). Survival patterns were consistent among patients with PD-L1-positive tumors (TPS≥1%, Figure S3) and in a sensitivity analysis that considered the year of treatment initiation, specifically for patients who began cCRT after March 2018.
Figure 1.
Kaplan-Meier analysis of (A) rwPFS, (B) OS, and (C) intracranial PFS between patients treated with consolidation ALK TKI, durvalumab, or observation. Two-sided log-rank test. rwPFS, real-world progression-free survival
OS
At the time of data cut-off, 13 patients were alive. Of patients in the ALK TKI cohort, 0% (n=0) died compared to 13% (n=4) in the durvalumab-treated cohort and 41% (n=9) in the observation cohort. Median OS was not reached in the ALK TKI cohort (95% CI: NR-NR) or the durvalumab cohort (95% CI: NR-NR). Median OS was 70.6 months in the observation cohort (95% CI: 24.9-NR months). OS in the ALK-TKI and durvalumab cohorts was significantly improved compared to observation (p=0.04, and p=0.3, respectively, Figure 1B), There was no significant difference in OS between the ALK TKI and durvalumab cohorts; however, the analysis lacked sufficient power to detect any differences (p=0.3, Figure 1B).
Intracranial PFS
Of the 12 patients with symptomatic intracranial progression, none was in the ALK TKI cohort, 6 in both the durvalumab and observation cohorts. Median rwicPFS was not reached in all 3 cohorts. There was a significantly longer rwicPFS for patients treated with ALK TKIs compared to observation (p= 0.05, Figure 1C) and no significant differences between ALK TKI and durvalumab or durvalumab and observation.
Survival outcomes in White patients
To address the variations in racial distribution across the three treatment groups (Table 1), we conducted a sensitivity analysis focusing exclusively on patients of White race. This group included 6 patients treated with ALK TKI, 20 with durvalumab, and 13 under observation. The analysis revealed a significant improvement in rwPFS for Whites receiving consolidation ALK TKI compared to those treated with durvalumab or under observation. Similarly, OS was significantly improved for Whites treated with consolidation ALK TKI versus those under observation. These findings are consistent with those observed in the overall cohort, indicating that the treatment benefits of ALK TKI are robust in patients of White race. Large cohorts are required to confirm this in non-White racial populations.
Treatment-related toxicities
TrAEs of any grade occurred in 8 (53%) and 11 (37%) treated with ALK-TKI and durvalumab, respectively (Figure 2A, B). Grade ≥3 trAEs occurred in 27% (4/15) of patients treated with ALK TKI and 6.7% (2/30) of patients treated with durvalumab. To adjust for treatment duration, we performed competing risk analysis, with treatment discontinuation for reasons other than toxicity considered as the competing event. There was no statistically significant difference in discontinuation rates due to toxicity between the ALK TKI and durvalumab cohorts (p=0.09) (Figure 2C). Overall, 13% (2/15) and 0% (0/30) required hospitalization due to trAEs in the ALK TKI and durvalumab cohorts respectively. Steroids were administered in 20% (3/15) and 23% (7/30) of patients treated with ALK TKI and durvalumab respectively. Of patients treated with ALK TKIs, 33% of patients (n=5) required dose reduction due to toxicities. Pneumonitis was reported in 6 patients, one (6.7%) in the ALK TKI cohort and five (17%) in the durvalumab cohort (Figure 2).
Figure 2.
Tornado plot depicting treatment-related adverse events for patients treated with consolidation ALK TKIs or durvalumab. (A) any grade and (B) ≥grade 3 or more treatment-related adverse events. (C) Cumulative incidence of discontinuation events in the ALK TKI and durvalumab cohorts. The bold lines show the cumulative incidence of discontinuation due to toxicity. The dashed lines show the cumulative incidence of the competing risk event (i.e. discontinuation due to reasons other than toxicity).
Of 48 patients treated with subsequent systemic therapies, trAEs related to the subsequent therapy occurred in 27% of patients. Two of 4 (50%) patients in ALK TKI cohort who went on to receive subsequent therapy developed trAE, of which one was pneumonitis (grade 2). In comparison, 8 out of 24 (33%) patients who received systemic therapy post-durvalumab developed trAEs including one case of pneumonitis (grade 3). Three out of 20 (15%) patients who received subsequent systemic therapies in the observation cohort developed trAEs, none of which was pneumonitis.
Discussion
This study suggests that consolidation therapy with ALK TKIs or durvalumab improved rwPFS and OS compared to observation. However, consolidation ALK TKIs provided a more pronounced benefit than durvalumab, suggesting a significant advantage of ALK TKIs in this context. Notably, 57% of patients on durvalumab experienced disease progression while receiving durvalumab and all patients who did not receive consolidation therapy experienced disease progression, with 77% of these events occurring within the first year post-cCRT. This underscores the urgent need for patients to receive more effective treatments for stage III ALK-positive NSCLC.
ALK-positive NSCLC is associated with a significant lifetime risk of developing CNS metastases(7). In our study, patients treated with consolidation ALK TKIs had significantly longer rwicPFS compared to observation. This outcome aligns with expectations, considering the documented efficacy of second and third-generation ALK TKIs in the CNS (8).
Our study found no unexpected toxicities with consolidation ALK TKI and durvalumab therapies, though toxicity led to a higher discontinuation rate in the ALK TKI cohort compared to the durvalumab cohort. The rate of severe toxicities was higher in the ALK TKI cohort but became non-significant after adjusting for treatment duration. This safety profile mirrors findings from the ALINA trial, where 30% of patients treated with alectinib experienced severe adverse events(6).
This study faces limitations, including its retrospective design, small sample size, and limited follow-up time. Nonetheless, the study provides valuable insight into the benefit of ALK TKIs after cCRT for stage III NSCLC, underscoring the urgency for prospective trials to explore curative treatment strategies for this patient population.
Supplementary Material
Supplementary Table 1. Distribution of patients included by center
Supplementary Figure S1. CONSORT diagram
Supplementary Figure S2. Swimmer plot of 15 patients treated with consolidation ALK tyrosine kinase inhibitor. RT: radiation therapy; TKI: tyrosine kinase inhibitor
Supplementary Figure S3. Kaplan-Meier analysis of rwPFS between patients with PD-L1 positive (≥1%)-NSCLC treated with consolidation ALK TKIs, durvalumab, or observation. Two-sided log-rank test. rwPFS, real-world progression-free survival.
Conflict of interest:
Amin H. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology. Consulting fees: Guidepoint Global, Putnam Associates.
Sarah B. Goldberg receives research funding from AstraZeneca, Boehringer Ingelheim, and Mirati and is anadvisory board member for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Amgen, Blueprint Medicine, Sanofi Genzyme, Daiichi-Sankyo, Takeda, Janssen, Summit Therapeutics, Merck, Regeneron, and Eli Lilly. Honoraria for lectures for Amgen and AstraZeneca.
Abdul Rafeh Naqash
Funding to Institution for Trials he is PI on: Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunocore, Phanes Therapeutics, Deka , Kymera, IDEAYA, IGM Biosciences, Selexine, Chipscreen Biosciences
Consultant Editor Compensation: JCO Precision Oncology
Travel Compensation: SITC/ AACR/ Conquer Cancer Foundation/BinayTara Foundation/ Foundation Med/ Caris Life Sciences/ Sarah Cannon Research Institute/Jazz Pharmaceuticals/ ASCO/ ASTRO
Advisory Board: Foundation Med, NGM biosciences
Current Research Grant Support: Swog Hope Foundation, FDA Broad Agency Award, OSCTR,
Genomics Research Agreements: Tempus , Caris , Foundation One
So Yeon Kim receives institutional funding from Loxo@Lilly, AstraZeneca, Boehringer Ingelheim, Genentech, Bristol-Myers Squibb, DynamiCure, Seagen, Genmab, Nykode Therapeutics.
Joshua E Reuss: Advisory Board/consultant - Sanofi/Genzyme, Personalis, Guardant, Astrazeneca, BMS, Arcus, Abbvie, Daiichi Sankyo, Catalym, Seagen, Gilead, Janssen, Novocure, Regeneron, Summit Therapeutics; Research Funding (to institution): Genentech/Roche, Verastem, Nuvalent, Exelixis; Honoraria – Merck, Astrazeneca
Alessio Cortellini: grants for consultancies/advisory boards: MSD, BMS, OncoC4, IQVIA, AstraZeneca, REGENERON, Access Infinity, Ardelis Health, Alpha Sight, Guidepoint, Roche. Speaker fees: AstraZeneca, Pierre-Fabre, MSD, Sanofi/REGENERON. Writing/Editorial activity: BMS, MSD. Travel support: Sanofi/REGENERON, MSD
Thomas U Marron currently or has previously served on Advisory and/or Data Safety Monitoring Boards for Rockefeller University, Regeneron, AbbVie, Merck, Bristol-Meyers Squibb, Boehringer Ingelheim, Atara, AstraZeneca, Genentech, Celldex, Chimeric, DrenBio, Glenmark, Simcere, Surface, G1 Therapeutics, NGMbio, DBV Technologies, Arcus, Fate, Ono, Larkspur, Avammune, and Astellas, and has research grants from Regeneron, Genentech, Bristol-Myers Squibb, Merck, and Boehringer Ingelheim.
Bailey Fitzgerald: Institutional Research Funding- Genentech/roche, PPD, bioatla. Travel- IASLC.
Thomas J. Dilling has served on Advisory Boards for Astra Zeneca. He is also a member of the NCCN Non-Small Cell Lung Cancer Panel.
Jair Bar: Advisor: AbbVie, Amgen, AstraZeneca, Bayer, MSD, Merck-Serono, Roche, Takeda; Writing/speaker engagement: BMS, Medison, Pfizer. Research funding: Immunai, OncoHost, MSD, AstraZeneca, Roche, Abbvie.
Jacqueline V. Aredo reports consulting fees from AstraZeneca.
JJL has served as a compensated consultant for Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, CLaiM Therapeutics, Ellipses, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Yuhan, Merus, Regeneron, Pfizer, and Turning Point Therapeutics; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; has received travel support from Pfizer and Merus.
David J. Kwiatkowski receives research funding from AADI and Genentech; and consults for Genentech, AADI, Expertconnect, Guidepoint, Bridgebio, Slingshot Insights, William Blair, MEDACorp, and Radyus Research.
Dr. Yu has done consulting for AstraZeneca, Daiichi, Janssen, Amgen, Black Diamond, Blueprint, Cullinan, Takeda, Taiho.
Dr. Feng reports receiving speaker honoraria from AstraZeneca Canada.
Ana I. Velazquez reports consulting fees from AstraZeneca, Merus, Novocure, and Regeneron.
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Associated Data
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Supplementary Materials
Supplementary Table 1. Distribution of patients included by center
Supplementary Figure S1. CONSORT diagram
Supplementary Figure S2. Swimmer plot of 15 patients treated with consolidation ALK tyrosine kinase inhibitor. RT: radiation therapy; TKI: tyrosine kinase inhibitor
Supplementary Figure S3. Kaplan-Meier analysis of rwPFS between patients with PD-L1 positive (≥1%)-NSCLC treated with consolidation ALK TKIs, durvalumab, or observation. Two-sided log-rank test. rwPFS, real-world progression-free survival.