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Margarita Majem
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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: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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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): Margarita Majem
- 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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FP13 - Immunotherapy (Phase II/III Trials) (ID 247)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP13.01 - 5-Year Survival Update From KEYNOTE-010: Pembrolizumab Versus Docetaxel in Previously Treated, PD-L1–Positive Advanced NSCLC (ID 1371)
00:00 - 00:00 | Author(s): Margarita Majem
- Abstract
- Presentation
Introduction
The KEYNOTE-010 study (NCT01905657) showed significantly improved OS with pembrolizumab 2 or 10 mg/kg Q3W versus docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. We provide long-term follow-up for KEYNOTE-010 including updated efficacy outcomes in patients who completed 35 cycles (2 years) of pembrolizumab and those who received second-course pembrolizumab.
Methods
Patients had previously treated advanced NSCLC with PD-L1 TPS ≥1% and were randomized 1:1:1 to receive pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W. Pembrolizumab treatment continued for 35 cycles (~2 years) or until disease progression/unacceptable toxicity. Eligible patients who completed pembrolizumab treatment or stopped pembrolizumab after achieving CR and receiving ≥6 months of treatment could receive second-course of pembrolizumab for up to 17 cycles (1 year) following disease progression after stopping pembrolizumab. Response was assessed Q9W. Survival was assessed every 2 months after treatment ended. Primary endpoints were OS and PFS in patients with PD-L1 TPS ≥50% and in those with PD-L1 TPS ≥1% (total population). Pembrolizumab in the pembrolizumab dose groups were pooled for this analysis.
Results
1033 patients were included in these analyses (pembrolizumab, 690; docetaxel, 343). As of April 8, 2020, median (range) time from randomization to data cutoff was 67.4 (60.0‒77.9) months. OS and PFS favored pembrolizumab in patients with PD-L1 TPS ≥50% and ≥1% (Table). Seventy-nine patients in the pembrolizumab group completed 35 cycles or 2 years of treatment with ORR of 98.7% (15 CR, 63 PR) in this group. Among those who completed 35 cycles or 2 years of pembrolizumab, 61 patients (77.2%) were alive (38 of whom were alive without PD). The 3-year OS rate after completing 35 cycles or 2 years (ie, at approximately 5 years) was 83.0%. Twenty-one patients received second-course pembrolizumab; 15 (71.4%) were alive at data cutoff. ORR after starting second-course was 52.4% (1 CR, 10 PR) and 6 had SD. Eight patients with CR/PR/SD after starting second-course subsequently had PD.
Table.
ConclusionPatients with PD-L1 TPS ≥50%
Patients With PD-L1 TPS ≥1%
Pembrolizumab
(N = 290)
Docetaxel
(N = 152)
Pembrolizumab
(N = 690)
Docetaxel
(N = 343)
Median OS,a mo (95% CI)
16.9 (12.3‒21.4)
8.2 (6.4‒9.8)
11.8 (10.4‒13.1)
8.4 (7.6‒9.5)
HR (95% CI)
0.55 (0.44‒0.69)
0.70 (0.61‒0.80)
5-year OS rate,a %
25.0
8.2
15.6
6.5
Median PFS,a,b mo (95% CI)
5.3 (4.2‒6.5)
4.2 (3.8‒5.1)
4.0 (3.1‒4.1)
4.1 (3.8‒4.5)
HR (95% CI)
0.57 (0.46‒0.71)
0.84 (0.73‒0.96)
5-year PFS rate,a %
18.2
Not reached
9.4
0.7
aKaplan-Meier estimate.
bAssessed by independent central review per RECIST version 1.1.
With more than 5 years of follow-up, pembrolizumab continued to provide clinically meaningful improvement in OS and PFS versus docetaxel in patients with previously treated, PD-L1–positive advanced NSCLC; 5-year OS rates were more than doubled in pembrolizumab-treated patients. Patients who completed 35 cycles or 2 years of pembrolizumab had durable clinical benefit. Second-course pembrolizumab provided meaningful disease control in the majority of patients who had disease progression after 2 years of pembrolizumab treatment.
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MA08 - Advances in Biomarkers for Immune Checkpoint Blockade and Targeted Therapy in Non Small Cell Lung Carcinoma (ID 166)
- Event: WCLC 2020
- Type: Mini Oral
- Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 16:45 - 17:45, Scientific Program Auditorium
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MA08.04 - LIPI and Outcomes of Durvalumab as Consolidation Therapy after ChRT in Patients with Locally-Advanced NSCLC (ID 1969)
16:45 - 17:45 | Author(s): Margarita Majem
- Abstract
- Presentation
Introduction
The lung immune prognostic index (LIPI), which combines pretreatment derived neutrophils/[leukocytes minus neutrophils] ratio (dNLR) >3 and lactate dehydrogenase (LDH) > upper limit of normal (ULN), is associated with outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI). We aimed to assess whether pretreatment LIPI correlates with durvalumab efficacy after concurrent chemoradiotherapy in the locally advanced setting.
Methods
Multicenter retrospective study of locally advanced NSCLC patients treated with durvalumab consolidation in 21 European/US centers from 12/2015 to 5/2020. Clinical and biological data were collected before durvalumab treatment. PD-L1 expression by immunohistochemistry was also collected at diagnosis. LIPI was calculated according to previous reports and three groups were characterized: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3 or LDH>ULN) and poor (dNLR>3+LDH>ULN). The primary endpoint was progression-free survival (PFS). Response was assessed according to the clinical routine of each center.
Results
A total of 267 patients were enrolled. One hundred eighty-five (69%) patients were male, 252 (94%) smokers, with median age of 67 [range 59-73] and 223 (98%) with Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1. 260/266 (98%) were stage III, of which 96 were IIIA, 127 stage IIIB and 37 stage IIIC. 163 (63%) had non-squamous histology and 12/131 (27%) harbored driver alterations: 5 EGFR, 4 BRAF, 3 MET, 2 ALK; missing in 136 cases. PD-L1 was ≥1% in 191/233 (82%) patients both from Europe and US, missing in 34 cases. LIPI was evaluable in 143 patients: 90 were considered good (63%), 50 intermediate (35%) and 3 (2%) as poor LIPI group. dNLR >3 was found in 47/218 (22%) and LDH > ULN in 23/143 (16%) cases. Radiotherapy was delivered concurrent in 219 (82%) of cases. No differences in clinical characteristics were found between 3 LIPI groups, including the response to previous chemoradiotherapy.
With a median follow-up of 13.4 months [95% confidence interval (CI), 12-15], the median PFS was 20 months [95% CI, 12.7-not reached (NR)]. Median PFS was 7.5 months [95% CI, 3.1-NR] for poor group vs. 10.7 months [95% CI, 5.1-NR] for intermediate group vs. 19.1 months [95% CI, 11.6-NR] for good LIPI group (P=0.020). Median overall survival (OS) was NR [95% CI 47-NR] in the entire cohort and therefore considered not mature. The first objective response rate under durvalumab was 44% (111/251), being 36% (18/50) for the intermediate-poor group and 38% (33/87) for the good group with no significant differences (P=0.099). No differences in PFS and OS between groups were found regarding PD-L1 status (P=0.5 and P=0.4, respectively).
Conclusion
Pretreatment LIPI is associated with clinical outcomes in locally advanced patients treated with durvalumab as consolidation after chemoradiotherapy. This cohort is still ongoing to confirm our preliminary findings in a larger cohort.
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OA06 - Updates on EGFR Targeted Perioperative Therapy and Precision Adjuvant Chemotherapy (ID 118)
- Event: WCLC 2020
- Type: Oral
- Track: Early Stage/Localized Disease
- Presentations: 2
- Moderators:
- Coordinates: 1/29/2021, 16:45 - 17:45, Scientific Program Auditorium
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OA06.03 - Patient-Reported Outcomes from ADAURA: Osimertinib as Adjuvant Therapy in Patients with Resected EGFR Mutated (EGFRm) NSCLC (ID 3505)
16:45 - 17:45 | Presenting Author(s): Margarita Majem
- Abstract
- Presentation
Introduction
Osimertinib is a third-generation, irreversible, central-nervous system-active, EGFR-tyrosine kinase inhibitor. The Phase III, double‑blind, randomized ADAURA study (NCT02511106) of completely resected stage IB–IIIA EGFRm non-small cell lung cancer (NSCLC), with/without adjuvant chemotherapy, reported a highly statistically significant and clinically meaningful disease-free survival (DFS) benefit with adjuvant osimertinib vs placebo (HR: 0.20 [99.12% CI: 0.14, 0.30]; p<0.0001). The effect of adjuvant treatment on health-related quality of life (HRQoL) is an important clinical consideration for patients who, following surgery with curative intent, are disease-free and require long-term treatment to reduce the risk of disease recurrence. We report patient-reported outcomes from ADAURA.
Methods
Adult patients with completely resected stage IB/II/IIIA (AJCC 7th edition; pathologic stage) EGFRm NSCLC (postoperative chemotherapy allowed, per physician and patient choice) were randomized 1:1 to osimertinib 80 mg once daily or placebo for three years (treatment completion)/until discontinuation. Per protocol, HRQoL was measured by the Short Form-36 (SF-36) health survey. Patients completed the SF‑36 health survey (eight domains and two aggregated summary scores: physical [PCS] and mental [MCS] component summary) at baseline, 12 and 24 weeks, then every 24 weeks until treatment completion/discontinuation. SF-36 was scored using norm-based scoring relative to the 2009 US general population (mean ± standard deviation, 50±10), resulting in T‑scores (higher T‑scores indicate better health). Here we report an exploratory post-hoc analysis of HRQoL in the overall patient population (N=682; stage IB–IIIA). A mixed model of repeated measures (MMRM) was used to analyze changes in SF-36 scores from baseline until Week 96 (to ensure balanced comparison between arms, due to earlier disease recurrence with placebo). Time to deterioration (TTD) was defined as time from randomization to first confirmed clinically important worsening/death. Clinically meaningful changes at the individual (PCS ±3.8 points, MCS ±4.6 points; TTD analyses) and group (PCS ±2 points, MCS ±3 points; MMRM analyses) level were assigned based on pre‑specified definitions from the SF-36 manual, 3rd edition. Data cut‑off: 17/01/2020.
Results
Compliance rates for completion of the SF-36 health survey were high (≥85%) across all visits in both arms. Baseline PCS and MCS scores were comparable in the osimertinib and placebo arms (range 46–47); scores in both arms were only slightly lower than the mean scores in the general population (0.3–0.4 SD below the normative mean [50]). PCS/MCS scores increased from baseline to Week 96 by 1.13/1.34 for osimertinib and 2.31/2.68 for placebo, with no clinically meaningful differences between arms (PCS -1.18 [95% CI: -2.02, -0.34]; MCS -1.34 [95% CI: ‑2.40, ‑0.28]. There were no differences in TTD of PCS (HR: 1.17 [95% CI: 0.82, 1.67]) or MCS (HR: 0.98 [95% CI: 0.70, 1.39]) between osimertinib and placebo.
Conclusion
In ADAURA, adjuvant osimertinib demonstrated a highly statistically significant improvement in DFS vs placebo in patients with resected stage IB–IIIA EGFRm NSCLC. HRQoL was maintained during osimertinib treatment with no clinically meaningful differences observed between arms. Collectively, these data further support adjuvant osimertinib as a new treatment strategy in this setting, with significant DFS benefit and maintained HRQoL.
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OA06.04 - Postoperative Chemotherapy Use and Outcomes from ADAURA: Osimertinib as Adjuvant Therapy for Resected EGFR Mutated NSCLC (ID 3464)
16:45 - 17:45 | Author(s): Margarita Majem
- Abstract
- Presentation
Introduction
Approximately 30% of patients with non-small cell lung cancer (NSCLC) present with resectable disease. Adjuvant chemotherapy is recommended in patients with resected stage IIꟷIIIA NSCLC, and selected stage IB patients; however, recurrence rates are high. In the Phase III, double-blind, randomized ADAURA study (NCT02511106), osimertinib (a third-generation, irreversible, CNS-active EGFR-tyrosine kinase inhibitor) demonstrated a highly statistically significant and clinically meaningful improvement in disease-free survival (DFS; hazard ratio [HR]: 0.20 [99.12% CI 0.14, 0.30]; p<0.001) in patients with completely resected stage IBꟷIIIA EGFR mutation-positive (EGFRm) NSCLC following adjuvant chemotherapy, when indicated. We report an exploratory analysis of adjuvant chemotherapy use and outcomes in ADAURA.
Methods
Patients with resected stage IB–IIIA (AJCC 7th edition; pathologic stage) EGFRm NSCLC were randomized 1:1 to receive osimertinib 80 mg once daily or placebo for three years (study completion) or until disease recurrence. Disease staging was based on electronic case report forms for baseline characteristics data, and interactive voice response system (IVRS) for efficacy data (per statistical analysis plan). Delivery of standard postoperative adjuvant chemotherapy prior to randomization was allowed, per physician and patient choice, but not mandatory. Assessment of adjuvant chemotherapy use was exploratory. DFS analysis in the overall population of patients (stage IB–IIIA disease) with/without adjuvant chemotherapy was a predefined subgroup analysis, performed using a Cox proportional hazards model. Data cutoff: 17/01/20.
Results
In ADAURA, 60% (410/682) of all patients randomized received adjuvant chemotherapy for a median duration of 4.0 (Q1: 4.0, Q3: 4.0) cycles, balanced across treatment arms. Overall, 409 patients received platinum-based chemotherapy, most with stage IIꟷIIIA (II: 71% [165/231]; IIIA: 80% [187/235]), and fewer with stage IB (26% [57/216]), disease. Across disease stages, the overall proportion of patients who received chemotherapy was 66% in patients aged <70 years (338/509), compared with 42% (72/173) in patients aged ≥70 years, reducing to 27% (21/78) in patients aged ≥75 years. WHO performance status (PS) did not impact chemotherapy use. The table reports DFS analysis with/without chemotherapy in the overall population and by disease stage, according to IVRS.
Stage IB
Stage II
Stage IIIA
Overall population
(stage IB–IIIA)With chemotherapy
OSI
n=28PBO
n=30OSI
n=81PBO
n=85OSI
n=94PBO
n=92OSI
n=203PBO
n=207DFS events, patients (%)
4 (14)
11 (37)
6 (7)
36 (42)
12 (13)
56 (61)
22 (11)
103 (50)
DFS HR
(95% CI)NC (NC, NC)
0.15 (0.06, 0.32)
0.13 (0.06, 0.23)
0.16 (0.10, 0.26)
Without chemotherapy
OSI
n=78PBO
n=76OSI
n=37PBO
n=33OSI
n=21PBO
n=27OSI
n=136PBO
n=136DFS events, patients (%)
7 (9)
18 (24)
5 (14)
16 (48)
3 (14)
22 (81)
15 (11)
56 (41)
DFS HR
(95% CI)0.38 (0.15, 0.88)
0.20 (0.07, 0.52)
0.10 (0.02, 0.29)
0.23 (0.13, 0.40)
CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; NC, not calculable; OSI, osimertinib; PBO, placebo
Disease stage recorded by interactive voice response system.
Subgroup categories with less than 20 events were excluded from the analysis. A hazard ratio of less than 1 favors osimertinib.
Conclusion
Adjuvant chemotherapy use in ADAURA was in line with uptake observed in previous studies and clinical practice. As expected, younger age and higher disease stage were associated with increased chemotherapy use, whereas use did not vary according to PS. DFS benefit with osimertinib vs placebo in patients who received prior chemotherapy was similar to that in patients who had not received prior chemotherapy, regardless of disease stage.
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