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Mariano Provencio
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ES06 - Perioperative Therapy for Early Stage NSCLC (ID 221)
- Event: WCLC 2020
- Type: Educational Session
- Track: Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 14:15 - 15:15, Scientific Program Auditorium
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ES06.01 - Neoadjuvant IO Monotherapy vs. Chemo-IO (ID 4046)
14:15 - 15:15 | Presenting Author(s): Mariano Provencio
- Abstract
- Presentation
Abstract
Anti-PD1/PD-L1 (anti-PD(L)1) antibodies activity is based on the blockade of PD-1 protein in lymphocytes or PD-L1 in tumor cells, preventing lymphocytes inactivation and promoting tumor elimination. A great part of the knowledge of its mechanism is due to neoadjuvant immunotherapy studies. In the situation with the intact tumor, on one side, anti-PD(L)1 rejuvenates the tumor-specific cytotoxic T cells from the tumor microenvironment, causing them to activate, proliferate and mobilize to eliminate distant micrometastasis. Additionally, anti-PD(L)1 increases tumor antigen presentation by dendritic cells in the tumor-draining lymph nodes activating new tumor-specific T cells that then migrate to tumor sites. Both processes trigger a powerful systemic anti-tumor immune response and the generation of memory T-cells that may provide long-term protection. Conversely, the neoantigen repertoire is reduced when the primary tumor is resected, limiting this anti-tumor immune response in the adjuvant setting and representing a strong argument for the neoadjuvant approach. Moreover, several immunological pathways are disrupted by surgical stress. While essential for wound healing, surgical stress leads to the expansion of Tregs, MDSC, and M2 macrophages, resulting in an overall state of immunosuppression with PD-1/CTLA-4 increase and T-cell exhaustion. Immune checkpoint inhibitors in neoadjuvant settings might be advantageous in activating tumor-infiltrating T-cells prior to surgery, and avoiding PD-1 expression on immune cells in the postoperative period.
Patients with NSCLC treated with neoadjuvant chemotherapy exhibited higher levels of PD-L1+ malignant cells and TILs than patients who underwent upfront tumor resection without neoadjuvant treatment. In patients who underwent neoadjuvant treatment, those with higher abundance of helper T cells and TAMs survived longer, suggesting that these cells may be important in chemotherapy response.
The neoadjuvant treatment has theoretical advantages like assessment of response to chemotherapy in vivo and this, in turn, helps identify patients who will potentially benefit from this therapy; perhaps the better locoregional drug delivery because of intact vessels presurgery; better tolerability; early treatment of micrometastatic disease; downstaging with improved resectability and offers the possibility for the identification of surrogate clinical and biological markers that may correlate with response to therapy and a potential long-term outcome. However neoadjuvant therapy has potential disadvantages: delay in local therapy due to toxicity, risk progression in chemoresistant patients, and pre-operative complications.
The prolonged duration of clinical trials for resectable stages I and III NSCLC, in which OS has been used as the primary endpoint, has resulted in slow progress and high expenses. There is a need for surrogate markers of efficacy outcome, aside from the traditional endpoints of OS or PFS, to accelerate the development of new therapies in early-stage NSCLC. Complete surgical resection, tumor downstaging, and complete and major pathologic responses after neoadjuvant chemotherapy have been associated with improved survival in resectable NSCLC.
Multiple checkpoint inhibitors have been evaluated as neoadjuvant treatment, but their use in this setting remains investigational.
Forde, et al. evaluated the feasibility of two doses of neoadjuvant PD-1 blockade in a recent pilot study in 21 patients with early-stage (I–IIIA) NSCLC (NCT02259621). Two preoperative doses of the anti-PD-1 inhibitor nivolumab (3mg/kg) were administered intravenously every two weeks, with surgery planned about 4 weeks after starting the neoadjuvant therapy. While only 10% of patients had objective responses on post-treatment CT-scans, MPR occurred in 45% of patients who went to surgery and 13% of patients had pathologic complete responses. Furthermore, MPR occurred in PD-L1-positive and PD-L1-negative tumors, and TMB was predictive of pathologic response to anti-PD-1 therapy.
LCMC3 trial (NCT02927301) is a phase II single-arm study of neoadjuvant atezolizumab monotherapy in patients with resectable early-stage NSCLC. The initial safety analysis of the first 54 of 180 planned patients who received two cycles of atezolizumab (PD-L1 inhibitor) monotherapy every three weeks in patients with stages IB to selected IIIB (T3N2) resectable NSCLC prior to surgical resection. By RECIST, 6/82 patients had a partial response, 72 had stable disease and 4 had progressive disease. The MPR rate was 18% (95% CI: 11-28%) 15/82, 4 patients had CPR (5%).
NEOSTAR study (NCT03158129) is a phase II study of induction checkpoint blockade for untreated patients with stage I-IIIA (single N2) NSCLC. The patients received three doses of nivolumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg q2w followed by surgery. Five of the 31 patients initially scheduled for surgery did not proceed to resection (one with hypoxemia grade 3, two with high surgical risk and two were no longer resectable). In the 26 resected patients, MPR rate was 28% with nivolumab and 31% with the combination. In ASCO 2019 updated data were presented, 39 of 44 underwent surgery, 89% resectability. The MPR rate was 24% overall, 17% with nivolumab, and 33% with the combination therapy. Secondary adverse events were 4%, including 2 bronchopleural fistulas and 8 air leaks.
As for combined ICI and chemotherapy, there are also different studies.
NADIM trial (NCT03081689) is a prospective, open-label, single-arm phase 2 trial, that evaluated the safety and efficacy of neoadjuvant chemotherapy paclitaxel + carboplatin plus nivolumab followed by adjuvant nivolumab in 46 patients with resectable stage IIIA (N2 or T4) NSCLC. The primary endpoint was progression‑free survival (PFS) at 24 months. Forty-one of 46 patients had undergone surgery and all tumors were resectable with R0 resection. At 24 months, progression-free survival was 77%. Intention to treat analysis shows 34 patients (83%) achieved MPR of which 26 (63%) had complete pathologic response (CPR). Downstaging was seen in 37 (90%) of cases. This is the first multi-center study to explore chemotherapy and immunotherapy in the neoadjuvant setting in stage IIIA.
In Shu C trial (NCT02716038), from Columbia University, patients received neoadjuvant treatment with atezolizumab, nab-paclitaxel, and carboplatin. Results show that 17/30 patients (57%) achieved MPR of which 10 (33%) had CPR.
Immunotherapy has revolutionized the treatment of advanced stages of lung cancer, becoming early stages of its next challenge.
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FP12 - Tumor Biology and Systems Biology - Basic and Translational Science (ID 188)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP12.01 - Circulating Tumor DNA to the Identification of EGFR Positive NSCLC Long-Term Survivors (ID 3013)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Survival data supports the use of first-line osimertinib as standard of care for EGFR positive non-small lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitor (TKI) followed by osimertinib for all patients. The impossibility of predicting which patients are at high risk of progression constitutes a major limitation of the sequential TKI approach.
Methods
Seven hundred and forty-five plasma samples from 192 stage IV, EGFR positive NSCLC patients who were treated with first-line TKI were analysed by digital PCR.
Results
Patients with EGFR sensitizing mutations in plasma with mutant allele frequency (MAF) <7% before treatment initiation had median OS 37.9 months (25.3-NR), compared 17.5 (95%CI: 11.3-25.5) months for patients with MAF≥7% (adjusted HR=0.43; 95%CI: 0.25-0.76, respectively). OS was achieved with 53.1% of the patients treated with a 2nd line treatment other than osimertinib. In the multivariable analysis, undetectable levels of circulating tumour DNA (ctDNA) after 3 and 6 months of treatment were associated with improved PFS and OS (P<0.001 in all cases). Patients who became ctDNA negative after 3 or 6 months of treatment with MAF<7% at diagnosis had more than two-thirds lower risk of progression and death compare to the rest of patients (adjusted HR=0.28; 95%CI: 0.17-0.46 and HR=0.24; 95%CI: 0.12-0.48 for PFS and OS, respectively).
Conclusion
Pre-treatment ctDNA levels identify patients at low risk of progression and death who could benefit from sequential TKI treatment. Information regarding EGFR sensitizing mutation clearance could improve patient selection.
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FP12.09 - Molecular Insight into NADIM Clinical Trial: Potential Immune Biomarkers of Pathological Response for NSCLC Patients. (ID 3552)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
- Presentation
Introduction
Many studies have demonstrated that chemo-immunotherapy is a promising approach for NSCLC patients but still exists a lack of prediction biomarkers of survival. We have recently showed that pathological response is a surrogate of progression free survival (PFS) including infiltrating immune cells as potential biomarker of pathological response in NADIM clinical trial (Provencio et al., 2020. Lancet Oncology, in press).
New biomarkers in peripheral blood are being described, focused on the immune system response. Preliminary data was presented at WCLC 2019 however additional results are included in this report. Here we describe the effect of chemo-immune neoadjuvant treatment on resectable NSCLC stage III patients’ immune system and describe blood biomarkers that could help to identify responders to this combination therapy.
Methods
Peripheral mononuclear cells (PBMCs) and plasma from NADIM clinical trial patients before and after chemo-immune neoadjuvant treatment were used. Phenotyping and activation levels of immune cell populations were analyzed by flow cytometry, focused on CD4 T cells, CD8 T cells, T cells NK like and NK cells. Moreover, characterization of the immune response was evaluated by a cytokine array.
Clinical evaluation of pathological response, classified patients in 3 groups, complete (CPR, 0% tumor cells), major (MPR, <10% viable tumor) and incomplete (IPR, >10% viable tumor). Wilcoxon and Kruskall-Wallis statistic tests were used.
Results
Even though we have previously described a decrease of T lymphocytes on tissue after treatment, we do not see these changes on blood. Thus, percentages of PBMCs (T cells, B cells, NK cells and macrophages) did not vary after neoadjuvant treatment. However, lower levels of activated CD4 T cells and NK cells were observed. Interestingly, this decrease was exclusively statistically significant for patients who achieved a CPR, but no differences were observed for MPR or IPR. As expected, detection of PD1+ cells after neoadjuvant Nivolumab (anti-PD1) treatment was almost completely abrogated, however, a trend for higher PD1+ cell proportions was observed in patients achieving CPR at diagnosis.
Furthermore, many cytokines involved in immune response and described as putative biomarkers for immunotherapy in NSCLC as IL-2, IL-15, IL-6, IL-13 or IFN-gamma, among others, were decreased after neoadjuvant treatment. Notably, stratifying by pathological responses, this decrease was statistically significant only for non-complete responses.
Conclusion
The analysis of immune cell markers on blood samples could be a source for potential surrogate markers of pathological response to neoadjuvant treatment on NSCLC patients.
Similarly, to what occurs in tissue, CPRs showed differences compared to MPR or IPR in some blood markers, both at the cellular and cytokine level. Thus, after treatment, patients achieving CPRs do not seem to reduce their levels of cytokines such as IL-2, IL-15, IL-6, IL-13 or IFN-g associated with anti-tumor response, but they do reduce their levels of activated CD4 and NK cells
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P09 - Health Services Research/Health Economics - Real World Outcomes (ID 121)
- Event: WCLC 2020
- Type: Posters
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P09.12 - SARS- CoV2 Impact in a Spanish Lung Cancer Cohort? (ID 2995)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Madrid has been the epicenter of the SARS-CoV2 pandemic in Spain. We analyzed our experience with SARS-CoV2 infection and cancer patients (p).
Methods
The analysis was carried out from March 1 to April 30 at the Puerta de Hierro University Hospital in Madrid. All patients with diagnosis of SARS-CoV2 infection by RT-PCR were included.
Results
During the study period, overall in-hospital mortality of cancer p with COVID-19 was 15.2% (95%CI, 6.3; 5.2), similar to 12.7% (95%CI,11.1;4.4) (p=0.615) of the global COVID-19 hospitalised population and greater than patients admitted without SARS-CoV-2 infection during the same period 4.3% (95%CI; 3.6;5.2) p<0.001.
Among the 653 patients receiving active cancer therapy, 24 (3.7%) developed COVID-19 and required admission, 4.2% of those were receiving chemotherapy, 9.5% immunotherapy and 2.1% targeted therapies. Lung and breast cancer were the most frequent (26.1%), followed by colorectal (19.6%) and breast cancer. Non-significant differences were found due to the cancer treatment received. Mortality in patients with lung cancer was the highest with 25%.
The univariate analysis comparing patients who developed a serious event to those who did not (Table2), showed that the higher Brescia, CURB-65 scale, the lactate dehydrogenase (LDH) or C-reactive protein (CRP) levels were at admission, the greater the risk of developing severe complications, with statistically significant results (table 2).
VARIABLE
OTHER CANCER PATIENTS, N=34 (%)
LUNG CANCER PATIENTS, N=12 (%)
Gender (male)
18 (52.9)
6 (50)
Age at hospitalization, mean (sd)
63.9 (10.2)
63.5 (15.5)
Active Smoking
0 (0.0)
2 (16.7)
Ex-smokers
12 (35.3)
6 (50)
COMORBIDITIES
Coronary heart disease
3 (8.8)
2 (16.7)
Hypertension
12 (35.3)
5 (41.7)
Hypothyroidism
3 (8.8)
0 (0.0)
COPD
3 (8.8)
2 (16.7)
Obesity
2 (5.9)
0 (0.0)
Diabetes
6 (17.7)
0 (0.0)
Dyslipidemia
8 (23.5)
3 (25.0)
LINES OF TREATMENT
First line
18 (52.9)
5 (41.7)
Other lines
8 (23.5)
5 (41.7)
Pending treatment
8 (23.5)
2 (16.7)
Recent cancer treatment <30d
11 (32.3
8 (66.7)
Active treatment
23 (67.6)
6 (50.0)
Others
10 (30.3)
0 (0.0)
SYMPTOMS
OTHER CANCER PATIENTS (N=34)
LUNG CANCER PATIENTS (N=12)
p-value
Neutropenia
2 (6.1)
0 (0.0)
1.000
Cough
23 (67.6)
5 (41.7)
0.170
Fever
26 (76.5)
9 (75.0)
0.918
Temperature
37.1 (1.0)
37.3 (1.1)
0.360
Dyspnoea
16 (47.0)
11 (91.7)
0.007
Diarrhoea
3(8.8)
1 (8.3)
1.000
Lymphopenia
22 (68.7)
4 (36.4)
0.080
PROGNOSTIC CRITERIA
IL6
0.416
<4,4
28 (82.3)
8 (66.7)
≥4,4
6 (17.7)
4 (33.3)
D-DIMER
0.9 (0.6; 2.2)
0.9 (0.5; 2.7)
0.574
<0,5
5 (17.9)
3 (27.3)
0.761
0,5-7
22 (78.6)
8 (72.7)
>7
1 (3.5)
0 (0.0)
PCR
107.7
0.449
<10
7 (21.9)
1 (9.1)
10-150
16 (50.0)
8 (72.7)
>150
9 (28.1)
2 (18.2)
LDH
266 (207; 326)
290 (238; 352)
0.195
<246
14 (46.7)
3 (27.3)
0.309
≥246
16 (53.3)
8 (72.7)
FERRITIN
562 (358; 933)
1111 (392; 2672)
0.158
CHARLSON INDEX
8 (6; 9)
8 (6; 9)
0.800
CURB65 SCALE
0.314
0-1
21 (61.8)
5 (41.7)
≥2
13 (38.2)
7 (58.3)
BRESCIA SCALE
0.178
0-1
30 (88.2)
8 (66.7)
≥2
4 (11.8)
4 (33.3)
Table 1. General characteristics, symptoms at diagnosis and prognostic data.COPD: chronic obstructive pulmonary disease,Charlson index (Comorbidities), Curb65 scale (includes age, confusion, urea, breathing frequency, blood pressure), Brescia Scale (depends on oxygen needs). P-values: comparison between lung cancer patients and the other.
VARIABLE
N VALID (N=46)
NON-SERIOUS EVENT (N=38)
SERIOUS EVENT (N=8)
P-VALUE
OR (95% CI)
Gender (male)
46
20 (52.6)
4 (50.0)
0.892
0.9 (0.19; 4.14)
Age at hospitalization
40
63.2 (11.6)
67 (11.4)
0.376
1.04 (0.96; 1.21)
Active Smoking
46
2 (5.3)
0 (0.0)
1
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Ex-smokers
46
16 (42.1)
2 (25.0)
0.453
0.46 (0.08; 2.57)
Hypertension
46
14 (36.8)
3 (37.5)
0.972
1.02 (0.21; 4.97)
COPD
46
4 (10.5)
1 (12.5)
0.871
1.21 (0.12; 12.57)
Dyslipidaemia
46
10 (26.3)
1 (12.5)
0.418
0.40 (0.04; 3.67)
Higher ferritin
26
598 (382; 1111)
975 (903; 2403)
0.396
1.00 (0.99; 1.00)
Higher IL6 ≥4,4
46
8 (21.1)
3 (37.5)
0.330
2.2 (0.44; 11.48)
Higher D- Dimer
41
1.1 (0.7; 2.2)
2.6 (1.5; 5.6)
0.069
1.39 (0.97; 1.99)
First LDH
41
254 (195; 316)
354 (266; 441)
0.020
1.01 (1.00; 1.03)
Higher LDH
40
271 (227; 332)
619 (354; 812)
0.007
1.01 (1.00; 1.03)
First CRP
43
95 (11; 146)
169 (89; 228)
0.038
1.01 (1.00; 1.02)
Higher CRP
42
116 (43; 167)
202 (130; 249)
0.018
1.02 (1.00; 1.03)
Brescia
44
0.5 (0; 1)
2 (2; 5)
0.004
19.5 (2.54; 149.7)
CURB-65
42
1 (1; 2)
2 (1; 3)
0.060
2.41 (0.97; 6.03)
Table 2.
Conclusion
Cancer patients, especially lung ones, and SARS-CoV2 infection have a worse overall prognosis than the general population.
Objective parameters such as LDH, CRP at admission, Brescia index or CURB-65 should alert us to a more serious evolution and suggest early an early intensive care unit (ICU) admission.
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P15 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Phase I) (ID 154)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P15.06 - Safety of BMS-986012, an Anti–Fucosyl-GM1 Monoclonal Antibody Plus Platinum/Etoposide in Untreated Extensive-Stage SCLC (ID 3416)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Small cell lung cancer (SCLC) is an aggressive lung tumor, with patients often presenting with metastatic disease at the time of diagnosis. Treatments for patients with extensive-stage SCLC have advanced little over the years, with 5-year overall survival (OS) rates remaining dismal. Immunotherapy has demonstrated clinical activity in ES-SCLC; however, the OS improvements have been only modest, with the first-line population remaining an unmet need in terms of treatment options (Horn et al. N Engl J Med 2018;379:2220–2229; Paz-Ares et al. Lancet 2019;394:1929–1939). Fucosyl-GM1, a tumor-associated antigen, is expressed in 50%–70% of cases with limited expression on normal tissue (Brezicka et al. Cancer Res 1989;49:1300–1305; Zhang et al. Int J Cancer 1997;73:42–49). Therefore, fucosyl-GM1 constitutes a potential target in SCLC. BMS-986012, a novel, first-in-class, nonfucosylated, fully human monoclonal antibody with high binding specificity for fucosyl-GM1 and enhanced antibody-dependent cellular cytotoxicity (Ponath et al. Clin Cancer Res 2018;24:5178–5189), was well tolerated and demonstrated promising antitumor activity in patients with relapsed/refractory SCLC (Chu et al. Ann Oncol 2016;27[suppl 6]. Abstract 1427PD). Here, we report the preliminary safety findings from a phase 1/2 trial of the combination of BMS-986012 and platinum/etoposide followed by BMS-986012 monotherapy maintenance in previously untreated patients with extensive-stage SCLC (NCT02815592).
Methods
Patients received BMS-986012 400 mg or 1000 mg on day 1, combined with either cisplatin 80 mg/m2 (part 1) or carboplatin area under the curve (AUC) 5 (part 2) on day 1 plus etoposide 100 mg/m2 on days 1, 2, and 3 (both parts) over four 21-day cycles, followed by BMS-986012 monotherapy maintenance. The primary endpoint was safety.
Results
As of Feb 6, 2020, 14 patients had received BMS-986012 (400 mg, n=12; 1000 mg, n=2) combined with platinum/etoposide, with 11 patients continuing into the monotherapy period. The median age was 62 years (range, 49–81 years), and 11 patients (79%) were men. BMS-986012 in combination with platinum/etoposide was well tolerated, and most treatment-related adverse events (TRAEs) were grade 1–2. The most common TRAEs (all grade; grade ≥3) was pruritus (86%; 7%). In most cases, pruritus resolved with antihistamines or low dose corticosteroids. Urticaria (7%; 7%), neutropenia (7%; 7%), xerosis (7%; 0%), conjunctivitis (7%; 0%), infusion-related reaction (7%; 0%), and dizziness (7%; 0%) were also observed. No serious TRAEs or dose-limiting toxicities were reported. One patient (BMS-986012 400 mg/carboplatin/etoposide) discontinued due to acute coronary syndrome determined to be unrelated to treatment. No notable differences were observed in the safety profiles of BMS-986012 plus cisplatin/etoposide (n=7) and BMS-986012 plus carboplatin/etoposide (n=7) in this study.
Conclusion
BMS-986012 in combination with platinum/etoposide was well tolerated in a treatment-naive patient population with extensive-stage SCLC. The safety profile was comparable to the profile observed historically with platinum/etoposide chemotherapy alone, except for clinically manageable pruritis. The safety findings support the ongoing evaluation of BMS-986012 as first-line therapy for extensive-stage SCLC.
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P25 - Mesothelioma, Thymoma and Other Thoracic Malignancies - Mesothelioma Preclinical, Prognostic and Predictive Factors (ID 139)
- Event: WCLC 2020
- Type: Posters
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P25.06 - Malignant Pleural Mesothelioma: Patient Characteristics, Treatments and Outcomes from a Spanish Center (ID 3005)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Malignant pleural mesothelioma (MPM) is a rare but aggressive tumour whose clinical and pathological diagnosis represents a challenge, due to delayed diagnosis and poor prognosis.
The aim of this study is to describe the demographic and clinical characteristics of patients with malignant pleural mesothelioma, as well as their subsequent treatments and outcomes in Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain.
Methods
We conducted a retrospective study including 51 patients with confirmed diagnosis of malignant pleural mesothelioma between 2008 and 2020. We collected information regarding epidemiology, treatments and survival patterns of patients with MPM. The cohort was divided in 3 groups depending on stage (I-II, III and IV), excluding non-treated patients. Progression-free survival (PFS) was calculated from the initiation of first-line treatment until the date of progression or death and overall survival (OS) was calculated from the initiation of first-line treatment until the date of last follow-up or death.
Results
Demographic characteristics of patients are shown in Table-1.
70.6% of patients were male, and the mean age at diagnosis was 65.5 years. Asbestos exposure was reported in 13.7% of patients. Most patients were diagnosed by pleural biopsy (85%). The most frequent histological subtype was epithelioid (75%).
Treatments and outcomes are shown in Table-2.
Surgery was performed in 6 patients stage I-II (54.5%) and in 8 patients stage III (33.3%). The first-line of chemotherapy most used regardless of stage was a platinum-doublet with pemetrexed.
Median OS was 17.0 months (95% CI, 9.08-24.92) with a median PFS of 8.0 months (95% CI, 2.25-13.75).
Only 9.1% of patients were included in clinical trials and 6.8% received immunotherapy.
Table-1. Demographic characteristics Sex
Female = 15 (29.4%)
Male = 36 (70.6%)
Mean age (years, 95% CI)
Mean: 65.51 (63.11-67.91)
Range: 44 (35-79)
Smoking habits
Never smoker: 16 (33.3%)
Current smoker: 9 (18.8%)
Former smoker: 23 (47.9%)
Non-available/unknown: 3 (5.8%)
Packs-year (CI 95%)
Mean: 37.121 (26.086-48.156)
Comorbidities
HTN: 26 (51%)
DL: 21 (41.2%)
Cardiopathy: 10 (19.6%)
Charlson: 8.49 (8.15-8.83)
Previous pleural pathology
5 (9.8%)
Simplified profession
Industry/construction: 15 (29.4%)
Others: 8 (15.7%)
Painter: 3 (5.9%)
Unknown: 25 (49%)
Exposure to inhaled agents recorded
12 (23.5%)
Asbestos exposure identified
7 (13.7%)
ECOG
0: 19 (37.3%)
1: 17 (33.3%)
2: 3 (5.8%)
3: 1 (2.0%)
Unknown: 11 (21.6%)
Symptoms
Dyspnea: 31 (60.8%)
Cough: 16 (31.4%)
Constitutional syndrome: 13 (25.5%)
Costal pain: 7 (13.7%)
Hemoptysis: 1 (2%)
Diagnosis image tests
PET-CT: 1 (2.0%)
Chest CT: 42 (82.4%)
Unknown: 8 (15.7)
Test sensitivity
Pleural cytology: 15 (38.5%)
Pleural biopsy: 39 (84.8%)
Stage
I: 4 (7.8%)
II: 8 (15.7%)
III: 24 (47.1%)
IV: 10 (19.6%)
Unknown: 5 (9.8%)
Metastatic location
Lung: 6 (66.7%)
Bone: 2 (22.2%)
Hepatic: 1 (11.1%)
Histology
Epithelioid: 36 (75.0%)
Biphasic: 6 (12.5%)
Sarcomatoid: 2 (4.2%)
Desmoplastic: 2 (4.2%)
Non-available/unknown: 5 (9.8%)
Table-2. Treatment and outcomes Variables
Stages I-II (N = 11)
Stage III (N = 24)
Stage IV (N = 9)
Age (mean, 95% CI, range)
65.18 (57.14-73.22)
44 (35-79)
64.67 (61.68-67.65)
23 (55-78)
64.7 (57.32-72.01)
31 (44-75)
Sex
Female = 7 (63.6%)
Male = 4 (36.4%)
Female = 6 (25.0%)
Male = 18 (75.0%)
Female = 2 (22.2%)
Male = 7 (77.8%)
First line
Treatment
Chemotherapy: 5 (45.5%)
Neoadjuvant chemotherapy + surgery + adjuvant radiotherapy: 2 (18.2%)
Surgery + adjuvant chemotherapy: 4 (36.4%)
Chemotherapy: 12 (50%)
Surgery + adjuvant radiotherapy + adjuvant chemotherapy: 5 (20.8%)
Surgery + adjuvant chemotherapy: 2 (8.3%)
Radiotherapy + chemotherapy: 2 (8.3%)
Neoadjuvant chemotherapy + surgery + adjuvant radiotherapy: 1 (4.1%)
Chemotherapy: 8 (88.9%)
Chemotherapy + Radiotherapy: 1 (11.1%)
Types of surgery
Extended pneumonectomy: 3 (27.7%)
Pleurodesis: 2 (18.2%)
Not specified: 1 (9.1%)
Pleurectomy + amplified decortication: 4 (16.7%)
Extended pneumonectomy: 4 (16.7%)
None
Chemotherapy
Cisplatin + pemetrexed: 3 (27.3%)
Carboplatin + pemetrexed: 5 (45.5%)
Gemcitabine: 1 (9.1%)
Cisplatin + pemetrexed: 11 (45.8%)
Carboplatin + pemetrexed: 9 (37.5%)
Carboplatin + pemetrexed + bevacizumab + atezolizumab: 1 (4.2%)
Carboplatin + pemetrexed: 5 (55.6%)
Cisplatin + pemetrexed: 3 (33.3%)
Carboplatin + pemetrexed + bevacizumab: 1 (11.1%)
Cycles (95% CI)
5.5 (4.32-6.68)
4.9 (4.33-5.47)
4.11 (2.93-5.29)
Maintenance treatment
1 (9.1%)
7 (29.2%)
2 (22.2%)
Maintenance treatment
Pemetrexed: 1 (9.1%)
Pemetrexed: 6 (25%)
Bevacizumab + atezolizumab: 1 (4.2%)
Pemetrexed: 2 (22.2%)
Best response
Progressive disease: 5 (45.5%)
Stable disease: 2 (18.2%)
Partial response: 2 (18.2%)
Progressive disease: 5 (20.8%)
Stable disease: 6 (25%)
Partial response: 5 (20.8%)
Complete response: 4 (16.7%)
Progressive disease: 4 (44.4%)
Stable disease: 1 (11.1%)
Partial response: 2 (22.2%)
Progression-free survival (months, 95% CI)
Mean: 12.0 (8.48-15.26)
Median: 8.0 (2.25-13.75)
Overall survival (months, 95% CI)
Mean: 21.6 (14.83-28.37)
Median: 17.0 (9.08-24.92)
Second line
Relapse
4
15
4
Time to relapse/progression
Local: 4 (36.4%)
Distance: 2 (18.2%)
Local: 15 (62.5%)
Distance: 6 (25.0%)
Local: 3 (33.3%)
Distance: 4 (44.4%)
Treated patients
4 (36.4%)
11 (45.8%)
3 (33.3%)
Treatment (%)
Chemotherapy + radiotherapy: 2 (18.2%)
Chemotherapy: 2 (18.2%)
Chemotherapy: 7 (29.2%)
Radiotherapy: 4 (16.7%)
Chemotherapy: 3 (33.3%)
Chemotherapy
Vinorelbine: 1 (9.1%)
Pemetrexed: 1 (9.1%)
Not specified: 2 (18.2%)
Vinorelbine: 5 (20.8%)
Gemcitabine: 1 (4.2%)
Irinotecan + lurbinectedin: 1 (4.2%)
Vinorelbine: 1 (11.1%)
Nivolumab: 1 (11.1%)
Other immunotherapy: 1 (11.1%)
Cycles
Mean: 3.5
Mean: 2.86
Mean: 7.0
Best response
Progressive disease: 3 (27.3%)
Stable disease: 1 (9.1%)
Progressive disease: 7 (29.2%)
Progressive disease: 2 (22.2%)
Partial response: 1 (11.1%)
Overall survival (months, 95% CI)
Mean: 12.69 (5.34-20.03)
Median: 7.0 (0-16.47)
Third, fourth and fifth line
Chemotherapy
Cisplatin + pemetrexed (retreatment): 1 (9.1%)
Gemcitabine: 1 (9.1%)
Irinotecan: 1 (9.1%)
Gemcitabine: 1 (4.2%)
Carboplatin + pemetrexed (retreatment): 1 (4.2%)
Gemcitabine: 2 (22.2%)
Cisplatin + pemetrexed (retreatment): 1 (11.1%)
Additional data
Included in clinical trials
4 (9.1%)
Patients who received immunotherapy
3 (6.8%)
Survival rate
First year: 58%
Second year: 30 %
Third year: 10%
Fourth year: 3%
Conclusion
Our results confirm that overall survival in patients with new diagnosis of MPM remains poor. Cytology has a low sensitivity and most patients were diagnosed at advanced stage, limiting the possibility of radical approaches.
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P60 - Tumor Biology and Systems Biology - Basic and Translational Science - Immune Bio (ID 198)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P60.07 - TMB and Selected Mutations in Resectable Stage IIIA NSCLC Patients Receiving Neo-Adjuvant Chemo-Immunotherapy from NADIM Trial (ID 2142)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Tumor Mutational Burden (TMB) assessment and identification of specific mutations associated to anti-PD1 blockade therapy resistance have become a novel approach to predict the clinical benefit to anti-PD1/PDL1 therapy. However, the clinical relevance of these parameters in terms of pathological response and PFS in neo-adjuvant chemo-immunotherapy has not been established. To answer this question we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant chemo-immunotherapy with Nivolumab.
Methods
Pretreatment TMB, defined as the number of nonsynonymous variants (missense and nonsense single nucleotide variants (SNVs)), plus insertion and deletion variants (INDELs) detected per megabase (Mb) of exonic sequence, was estimated from 27 patients that had enough diagnostic material for next generation sequencing using the Oncomine Tumor mutation Load assay (ThermoFisher) following manufacturer’s instructions. The panel covers 1.7 Mb of 409 genes with known cancer associations. Regarding pathological responses, patients were classified into 3 groups: pathologic complete response (pCR) (0% viable tumour at any localization tested), major pathologic response (MPR, <10% viable tumour) and pathologic incomplete response (pIR) (>10% of viable tumour). At data analysis, median follow-up time was 22.7 months.
Results
Median TMB was 5.89 (range 1.68 – 73.95). No differences in TMB value between histologies (adenocarcinoma vs squamous cell), smoking status (former vs current), age or sex were observed. Somatic mutations were identified in lung cancer driver genes such as TP53, KRAS, EGFR, CDKN2A, NOTCH1, BRAF and in specific genes associated with resistance to immunotherapy such as STK11, KEAP1, and RB1. No genomic alterations in ALK, ROS1, PTEN or ERBB2 were found.
Based on literature, a poor prognosis mutation signature (presence of EGFR, STK11, KEAP1 or RB1 mutations) was generated. A third of the sequenced patients (9/27) harboured at least one mutation in one of these genes.
Pathological response data was available from 23 out of 27 patients sequenced. Both the TMB value and the presence of these resistance mutations were not associated with the degree of pathological response.
Regarding PFS, TMB alone was not predictive of disease progression using different thresholds. However, the presence of these resistance mutations was associated with shorter PFS (log-rank p-value=0.032). The median PFS for mutated patients was 21.4 months (95% CI 16-26 months) while median PFS was not reached in non-mutated patients.
Additionally, the combination of this mutational signature with TMB (absence of resistance mutations and TMB-Higher than median) was able to distinguish patients that strongly benefit from this therapy. Although the median PFS was not reached in both groups yet, statistically significant differences were observed (log-rank p-value=0.046). PFS at 18 and 24 months was 100% (95% CI not estimable) for Non-mutated patients with TMB-High vs 70% (95% CI 50-89%) and 58% (95% CI 35-81%) for the rest of patients (mutated patients plus Non-mutated patients with TMB-Low).
Conclusion
TMB did not predict benefit from chemo-immunotherapy induction in our cohort. However, the presence of EGFR/STK11/KEAP1/RB1 mutations alone, or in combination with TMB, may help identify patients that unlikely benefit from neo-adjuvant chemo-immunotherapy
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P60.11 - TCR Repertoire Predicts Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemoimmunotherapy from NADIM Trial (ID 3417)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Characterization of the T-cell receptor (TCR) repertoire has become a novel approach to monitor immunotherapy responses, however there is lack of knowledge about its clinical relevance as predictive biomarker of pathological response in neoadjuvant chemoimmunotherapy. For this purpose, we analysed samples from the NADIM study (NCT03081689), in which resectable stage IIIA NSCLC patients were treated with neoadjuvant Paclitaxel + Carboplatin + Nivolumab for 3 cycles, achieving a 63% of complete pathologic responses (CPR). PD-L1 TPS and TMB as CPR biomarkers showed AUC ROC of 0.77 and 0.55, respectively, reinforcing the need for new biomarkers (Provencio, M. et al. 2020).
Methods
TCR repertoires from primary tumours or lymph nodes of 19 NSCLC patients were obtained, at both time points: diagnosis and after neoadjuvant treatment. TCR repertoire was analysed in terms of convergence, diversity, evenness and clonal space, defined as the summed frequency of clones belonging to a frecuency group (top 1%, top 1% to 2%, 2% to 5%, and >5%) relative to the total T-cell repertoire. The results were correlated with pathological response groups and ROC curve analysis was performed to test if TCR repertoire-derived parameters could identify patients with CPR.
Results
There were no statistically significant differences observed in TCR repertoire in biopsy samples in terms of diversity (p = 0,797) or convergence (p = 0,202) between the three pathological response groups or between biopsy and surgery samples. However, we observed differences in terms of evenness in biopsy samples between the pathologic response groups (p=0.037), which were lower in those patients who achieved CPR. The AUC for evenness was 0.844 (IC: 0.667-1.000), p=0,011. An evenness value of <0.8639 showed a sensitivity of 50% and specificity of 100% identifying patients with CPR.
Moreover, the clonal space of the TOP 1% clones in diagnostic samples was higher in patients that achieved CPR (p=0.002). The AUC of this novel biomarker was 0.9667 (IC: 0.897-1.036) (p=0.0006). A TOP 1% clonal space higher than 0.1607 showed a sensitivity of 90% and specificity of 88.9% identifying patients with CPR.
Conclusion
Our results support the association between the uneven distribution of T-lymphocytes clones proportions present in the tissue at diagnosis and response to chemoimmunotherapy. Specifically, higher clonal space occupied by the TOP 1% clones seems to outperform PD-L1 and TMB as predictive biomarker of CPR in NSCLC patients receiving neoadjuvant chemoimmunotherapy.
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P66 - Tumor Biology and Systems Biology - Basic and Translational Science - Outcomes (ID 205)
- Event: WCLC 2020
- Type: Posters
- Track: Tumor Biology and Systems Biology - Basic and Translational Science
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P66.04 - Real World Data: Immunotherapy in Lung Cancer Patients over 65 Years Old in Spain (ID 3641)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
In the last decade, immunotherapy (IT) has become a key therapeutic tool in lung cancer treatment. The number of elderly patients with this pathology in Spain has been progressively increased in recent years, becoming a representative subgroup nowadays. Studies carried out with IT in these patients are a minority and controversial, generating a need in clinical practice.
The aim of the study is to establish clinical and toxicity differences between patients older and younger than 65 years, treated with IT.
Methods
Retrospective study that includes all epidemiological, clinical and pathological data of patients > 65 and <65 years diagnosed with lung cancer at Puerta de Hierro Hospital from January 2014 to March 2020, and who received treatment with IT, either in the first line or successive.
Results
A total of 155 patients were analyzed. Table 1 summarizes the main characteristics between both populations. The mean number of treatments received in both groups was similar (3.0 in <65 years vs 2.7 in> 65).
When both groups were compared, no statistically significant differences in the percentage of patients who needed to interrupt IT due to toxicity were observed, being 15.9% of those <65 years and 17.9% of those> 65 years (p = 0.576) who required this interruption.
There were also no differences in toxicity between grade 3 or 4 (10.2% vs 10.4%, p = 0.99) or in the number of admissions due to immune-related toxicity (IR) (9.0% vs 4.5%, p = 0.19).
Neither group required immunosuppressive treatment for severe toxicity, but they did require steroids at high doses. There were no deaths secondary to IT toxicity, being the majority due to disease progression.Table 1.
Characteristics
<65 years (88)
>65 years (67)
Gender
Male
Woman
54.5%
45.6%
74.6%
25.4%
Median age
58
72
ECOG
0-1
≥2
93.2%
4.5%
97.0%
3.0%
Charlson index
8
10
Stage
I – 3.4%
II – 6.8%
III - 33.0%
IV – 56.8%
I – 3.0%
II – 11.9%
III – 23.9%
IV – 61.2%
Histology
Adenocarcinoma
Squamous cell carcinoma
Small cell
Others
59.1%
27.3%
2.3%
11.4%
56.7%
25.4%
4.5%
13.4%
PDL-1
Positive
Negative
Unknown
29.5%
9.1%
13.6%
32.8%
16.4%
7.5%
Disease situation at the toxicity moment
Complete response
Partial response
Stable disease
Progression
8.2%
13.7%
20.5%
47.9%
1.6%
27.9%
23.0%
32.8%
Toxicity types
Asthenia
Anemia
Pneumonitis
Thyroid disorders
Cutaneous
Colitis
Nephritis
Hepatitis
Others
11.4%
1.1%
14.8%
10.2%
9.1%
6.8%
0%
3.4%
13.6%
13.4%
0%
11.9%
11.9%
9.0%
4.5%
4.5%
1.5%
9.0%
Toxicity grade
1
2
3
4
17.0%
6.8%
5.7%
3.4%
14.9%
13.4%
8.9%
1.5%
Conclusion
Patients > 65 years with lung cancer who received IT treatment in our center do not experience more serious adverse events, do not require more treatment interruptions or more admissions, compared to those <65 years. Consequently, IT should be a valid treatment option in this population and its management should be optimized, with the aim of offering the best possible quality of care to this subgroup of patients.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.42 - OsimertinibTreatment in Non-Small Cell Lung Cancer (NSCLC) EGFR-T790M+. Activity in Patients with CNS Metastases. OSIREX (ID 1860)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Based on the lack of real-life results the Spanish Lung Cancer Group (SLCG) proposed to organize a retrospective study in which we can describe the experience in efficacy and safety of osimertinib in p with NSCLC EGFRm T790M and central nervous system CNS) metastases.
Methods
Observational, non-interventional, multicentre, one-arm, non comparative, retrospective study in T790M positive NSCLC p with advanced or metastatic disease. A total of 155 p were included. The observation period was from August 2016 to December 2018 in 30 Spanish hospitals. This corresponds to a total period of 29 months.
Results
155 p were included (108 women (69.7%), median age: 67 (37-88), 64% (99/155) were non-smokers and 99 % (154/155) had adenocarcinoma. Most p had received at least one prior treatment (97.4%, 151/155): 76.8% previous EGFR-TKIs, and 20.6% had received prior cytotoxic chemotherapy. At data cutoff, median duration of follow-up was 11.7 months (0.4-32).
A total of 155 p were evaluable for response analysis, 87(56%) as 1st and 2nd line therapy and 68 as ≥3rd line. 45 patients (30%) had CNS metastases at baseline. PFS was inferior en patients with CNS metastases than in those without (median, 7.2 months (95% CI, 3.9 to 10.6) vs 10.3 months (95% CI, 7.8 to 12.8) HR: 1.54 (95% CI, 1.03 to 2.32).
Conclusion
This retrospective study to assess the real-world clinical impact of osimertinib in p with advanced NSCLC and CNS metastases. Osimertinib had demonstrated greater penetration of blood brain barrier than gefitinib or erlotinib and these results could recommend us to use in first line.
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P84 - Targeted Therapy - Clinically Focused - ALK (ID 261)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P84.14 - Identification of Mechanisms of Resistance to ALK Inhibitors. Next-Generation Sequencing-Based Liquid Biopsy Profiling. (ID 3612)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
Despite impressive and durable responses, patients treated with ALK inhibitors (ALK-Is) ultimately progress. We investigated potential resistance mechanisms in a series of ALK-positive non-small cell lung cancer (NSCLC) patients progressing on different types of ALK-Is.
Methods
26 plasma and 2 cerebrospinal fluid samples collected upon disease progression to an ALK-I, from 24 advanced ALK-positive NSCLC patients, were analyzed by next-generation sequencing (NGS). A tool to retrieve variants at the ALK locus was developed.
Results
61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1) FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3 and CCND1. Overall, We identified at least one mutation in ALK locus in 10 (38.5%) plasma samples, being the G1269A and G1202R mutations the most prevalent among patients progressing to first- and second-generation ALK-I treatment, respectively. An exon 19 deletion in EGFR was identified in a patient showing primary resistance to ALK-I. Likewise, the G466V mutation in BRAF and the F129L mutation in MAP2K1 (MEK1) were identified as the underlying mechanism of resistance in three patients who gained no or little benefit from second-line treatment with an ALK-I. Putative ALK-I resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and a FGFR3, were detected in a patient progressing on a first-line treatment with crizotinib.
Conclusion
NGS analysis of liquid biopsies upon disease progression identified putative ALK-I resistance mutations in most cases, being a valuable approach to devise therapeutic strategies upon ALK-I failure.
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P84.16 - Treatment Options for Patients with Brain Metastases in Oncogene-Driven Non-Small Cell Lung Cancer (ID 3699)
00:00 - 00:00 | Author(s): Mariano Provencio
- Abstract
Introduction
The brain is a frequent site of metastases in non-small cell lung cancer (NSCLC), specially in those with driver gene mutations. Treatment strategies include surgical resection, central nervous system (CNS) radiotherapy (RT), what includes: whole-brain radiation therapy (WBRT) and stereotactic radiotherapy, and drug therapy like tyrosine kinase inhibitors (TKIs).
Methods
We conducted a single centre retrospective review including 60 (25.3%) NSCLC patients with driver gene mutations (EGFR, ALK, ROS1) and brain metastases from a total of 237 patients treated with TKIs in Hospital Universitario Puerta de Hierro (Spain) between 2008 and 2020. We collected information regarding epidemiology, treatments, response and survival patterns. We analysed patients treated with TKIs alone and specifically patients who were treated with newly developed TKIs that can efficiently penetrate the blood-brain barrier (osimertinib, alectinib, ceritinib, brigatinib, lorlatinib). Radiotherapy-free survival was calculated from the initiation of first-line TKI until the date of CNS RT.
Results
Global characteristics regarding clinical characteristics, treatment and survival are shown in Table-1.
56.7% were female and mean age at diagnosis was 60.0 years. Driver gene mutations were EGFR (80.0%), ALK (20.0%) and ROS1 (0%). 56.7% received CNS RT and median OS was 31.0 months (95% CI, 21.4-46.6) with a median TKI time-treatment 27.0 months (95% CI, 22.0-31.9).
Specific data from patients treated with TKIs alone at the diagnosis of brain metastases and those treated with new generation TKIs are shown in Table-2.
CNS RT was performed in 24% with a RT-free survival mean of 45.15 months (95% CI, 28.85-61.51). Newly developed TKIs achieved a partial or complete CNS response in 42.9%.
Table-1. Global characteristics Clinical characteristics (n = 60)
Sex
Male: 26 (43.3) Female: 34 (56.7)
Age (years, range)
Mean: 60.0 (56.95-63.09)
Histology
Adenocarcinoma: 58 (96.7)
Neuroendocrine carcinoma: 1 (1.7)
Squamous cell carcinoma: 1 (1.7)
Driver gene mutations
EGFR: 48 (80.0)
ALK: 12 (20.0)
ROS1: 0
Mutations reported
Non-reported: 22 (36.7)
Exon 21 L858R: 13 (21.7)
Exon 21 L861Q: 1 (1.7)
Exon 21 (non-specified): 2 (3.3)
Exon 19 deletion: 18 (30.0)
Exon 18 (G719X): 2 (3.3)
Exon 18 (non-specified): 1 (1.7)
Exon 20 (insertion): 1 (1.7)
Smoking status
Smoker: 10 (16.7)
Former smoker: 15 (25.0)
Never smoker: 31 (51.7)
Non-reported: 4 (6.7)
Packs-year (95% CI)
Mean: 26.75 (20.76-32.73)
Comorbidities
Hypertension: 14 (23.3)
Dyslipidemia: 9 (15.0)
Diabetes: 5 (8.3)
Alcohol consumption: 9 (15.0)
First degree family history of cancer
29 (48.3)
ECOG:
0: 31 (51.7)
1: 22 (36.7)
2: 1 (1.7)
Non-reported: 6 (10)
CNS initial affection
43 (71.7%)
CNS type of affection
Unique: 11 (18.3)
Multiple: 47 (78.3)
Non-reported: 2 (3.3)
Radiological findings
Intracranial hypertension: 13 (21.7)
Meningeal carcinomatosis: 16 (26.7)
First TKI treatment (n = 60)
TKI
Erlotinib: 22 (36.7)
Afatinib: 10 (16.7)
Gefitinib: 12 (20.0)
Osimertinib: 5 (8.3)
Crizotinib: 8 (13.3)
Alectinib: 3 (5.0)
Best CNS response
Progressive disease: 3 (5.0)
Stable disease: 12 (20.0)
Partial response: 16 (26.7)
Complete response: 5 (8.3)
Unknown: 24 (40.0)
Best global response
Progressive disease: 5 (8.3)
Stable disease: 11 (18.3)
Partial response: 25 (41.7)
Complete response: 6 (10.0)
Unknown: 13 (21.7)
Reported toxicities
31 (51.7)
Grade of toxicity
1: 14 (23.3)
2: 5 (8.3)
3: 7 (11.7)
4: 1 (1.7)
Non-grade reported: 4 (6.7)
Treatment interruption due toxicity
11 (18.3)
Treatment dose-reduction
4 (6.7)
Second TKI treatment (n =28)
TKI
Erlotinib: 4 (16.0)
Afatinib: 6 (21.4)
Gefitinib: 2 (7.1)
Osimertinib: 6 (21.4)
Brigatinib: 1 (3.5)
Crizotinib: 1 (3.5)
Alectinib: 6 (21.4)
Ceritinib: 2 (7.1)
Non-TKI second line: 32
Best CNS response
Progressive disease: 6 (21.4)
Stable disease: 3 (10.7)
Partial response: 6 (21.4)
Complete response: 1 (3.5)
Unknown: 12 (42.9)
Best global response
Progressive disease: 6 (21.4)
Stable disease: 7 (25.0)
Partial response: 10 (35.7)
Complete response: 0
Unknown: 5 (17.8)
Reported toxicities
10 (35.7)
Grade of toxicity
1: 4 (16.0)
2: 2 (7.1)
3: 2 (7.1)
4: 1 (3.5)
Non-grade reported: 1 (3.5)
Treatment interruption due toxicity
3 (10.7)
Treatment dose-reduction
1 (3.5)
Third TKI treatment (n =9)
TKI
Erlotinib (retreatment): 2 (22.2)
Afatinib: 1 (11.1)
Gefitinib: 1 (11.1)
Osimertinib: 3 (33.3)
Brigatinib: 1 (11.1)
Lorlatinib: 1 (11.1)
Best CNS response in first line
Progressive disease: 3 (33.3)
Partial response: 2 (22.2)
Unknown: 4 (44.4)
Local CNS treatment (n = 60)
CNS Radiotherapy
34 (56.7)
CNS Radiotherapy type
Whole-brain radiotherapy (WBRT): 24 (40.0)
Stereotactic radiotherapy: 8 (13.3)
Both: 2 (3.3)
Reported toxicity
6 (10.0)
Best CNS response due to RT
Progressive disease: 11 (18.3)
Stable disease: 6 (10.0)
Partial response: 8 (13.3)
Complete response: 3 (5.0)
Unknown: 6 (10.0)
CNS surgery
2 (3.3)
Survival
Total TKI treatment time (months, 95% CI)
Mean: 33.3 (23.4-43.2)
Median: 27.0 (22.0-31.9)
Overall survival, (months, 95% CI)
Mean:
Global: 42.6 (28.6-56.6)
EGFR: 35.1 (24.7-45.5)
ALK: 64.3 (29.1-99.6)
Median:
Global: 31.0 (21.4-46.6)
EGFR: 29.0 (17.9-40.1)
ALK: 34.0 (21.4-46.6)
ConclusionTable-2. Patients treated with TKIs alone at the diagnosis of brain metastases and those treated with new generation TKIs Patients treated with TKI alone (n = 25)
Targetable driver mutation
EGFR: 22 (88.0)
ALK: 3 (12.0)
Radiotherapy at progression
6 (24.0)
Radiotherapy type
Whole-brain radiotherapy (WBRT): 5 (20.0)
Stereotactic radiotherapy: 1 (4.0)
Best CNS RT response
Progressive disease: 2 (8.0)
Partial response: 3 (12.0)
Unknown: 1 (4.0)
Radiotherapy-free survival (months, 95% CI)
Mean: 45.15 (28.85-61.51)
First TKI treatment (n = 25)
TKI
Erlotinib: 8 (32.0)
Afatinib: 4 (16.0)
Gefitinib: 5 (20.0)
Osimertinib: 5 (20.0)
Crizotinib: 1 (4.0)
Alectinib: 2 (8.0)
Best CNS response
Progressive disease: 6 (24.0)
Stable disease: 0
Partial response: 11 (44.4)
Complete response: 3 (12.0)
Unknown: 5 (20.0)
Best global response
Progressive disease: 3 (12.0)
Stable disease: 5 (20.0)
Partial response: 11 (44.0)
Complete response: 1 (4.0)
Unknown: 5 (20.0)
Second TKI treatment (n = 8)
TKI
Erlotinib: 1 (12.5)
Gefitinib: 1 (12.5)
Afatinib: 2 (25.0)
Osimertinib: 3 (37.4)
Alectinib: 1 (12.5)
Best CNS response
Progressive disease: 1 (12.5)
Stable disease: 1 (12.5)
Partial response: 1 (12.4)
Complete response: 0
Unknown: 5 (62.5)
Best global response
Progressive disease: 2 (25.0)
Stable disease: 0
Partial response: 5 (62.5)
Complete response: 0
Unknown: 1 (12.5)
Third TKI treatment (n = 4)
TKI
Erlotinib (retreatment): 1 (25.0)
Gefitinib: 1 (25.0)
Osimertinib: 1 (25.0)
Lorlatinib: 1 (25.0)
Best CNS response
Partial response: 1 (25.0)
Unknown: 3 (75.0)
Brain penetration TKI data (n = 28)
TKI included
Alectinib: 9 (32.1)
Brigatinib: 2 (7.1)
Ceritinib: 2 (7.1)
Lorlatinib: 1 (3.6)
Osimertinib: 14 (50.0)
Our study shows that deferring CNS RT in oncogene-driven NSCLC and CNS involvement is a valid option due to CNS metastases response to TKIs, especially to those that can penetrate the blood-brain barrier, in order to avoid side-effects derived from CNS radiation.
