Virtual Library
Start Your Search
Delvys Rodríguez-Abreu
Author of
-
+
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
-
+
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): Delvys Rodríguez-Abreu
- 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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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
-
+
FP13.02 - Pembrolizumab + Pemetrexed-Platinum vs Pemetrexed-Platinum for Metastatic NSCLC: 4-Year Follow-up From KEYNOTE-189 (ID 3194)
00:00 - 00:00 | Author(s): Delvys Rodríguez-Abreu
- Abstract
- Presentation
Introduction
In the randomized, double-blind, phase 3 KEYNOTE-189 trial (NCT02578680) pembrolizumab plus pemetrexed-platinum chemotherapy significantly improved OS and PFS vs placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, regardless of PD-L1 expression. We present efficacy and safety outcomes after ~4 years of follow-up.
Methods
Patients were randomized (2:1) to intravenous pembrolizumab 200 mg or placebo Q3W for up to 35 cycles (2 years). All patients received pemetrexed and investigator’s choice of carboplatin/cisplatin for 4 cycles, followed by maintenance pemetrexed. Treatment continued until radiographic progression/unacceptable toxicity. Crossover from placebo plus chemotherapy to pembrolizumab monotherapy was permitted after PD. Patients who experienced SD or better during initial treatment or crossover phases with pembrolizumab and then experienced PD at any time during the follow-up period could receive second-course pembrolizumab (17 cycles). The primary endpoints were OS and PFS.
Results
616 patients were randomized (pembrolizumab plus pemetrexed-platinum, n=410; placebo plus pemetrexed-platinum, n=206). Median (range) time from randomization to data cutoff (August 28, 2020) was 46.3 (41.8–54.1) months. 84 patients (40.8%) randomized to the control group crossed over to pembrolizumab monotherapy on-study. Efficacy outcomes are summarized in the Table. Median (95% CI) OS was 22.0 (19.5‒24.5) months with pembrolizumab plus pemetrexed-platinum vs 10.6 (8.7‒13.6) months with placebo plus pemetrexed-platinum (hazard ratio [HR], 0.60; 95% CI, 0.50‒0.72). 3-year OS rate was 31.3% vs 17.4%. Median (95% CI) PFS was 9.0 (8.1‒10.4) months vs 4.9 (4.7‒5.5) months, respectively (HR, 0.50; 95% CI, 0.41‒0.59). Grade 3‒5 AEs occurred in 72.1% patients in the pembrolizumab plus pemetrexed-platinum group and 67.3% patients in the placebo plus pemetrexed-platinum group. Among 56 patients who completed 35 cycles (2 years) of pembrolizumab, 49 (87.5%) had an objective response (CR, n=6; PR, n=43) and 7 (12.5%) had SD. 45 patients (80.4%) were alive at data cutoff (28 without PD), and 2-year OS after completion of 35 cycles was 79.6%. At data cutoff, 7 patients had initiated second-course pembrolizumab.
ConclusionTable. Efficacy Outcomes in the ITT Population and in Subgroups Defined by PD-L1 TPSa
ITT
N=616TPS ≥50%
n=202TPS 1%-49%
n=186TPS <1%
n=190OS HR (95% CI)b
0.60 (0.50–0.72)
0.71 (0.50–1.00)
0.66 (0.47–0.93)
0.52 (0.37–0.72)
3-yr OS rate,b %
31.3 vs 17.4
43.7 vs 30.0
28.3 vs 17.2
23.3 vs 5.3
PFS HR (95% CI)b,c
0.50 (0.41–0.59)
0.36 (0.26–0.49)
0.54 (0.39–0.76)
0.68 (0.49–0.93)
PFS2 HR (95% CI)b,c,d
0.52 (0.43–0.63)
0.55 (0.39–0.77)
0.59 (0.42–0.83)
0.49 (0.35–0.68)
ORR,c %
48.3 vs 19.9
62.1 vs 25.7
50.0 vs 20.7
33.1 vs 14.3
Median DOR,b,c mo
12.6 vs 7.1
15.1 vs 7.1
13.6 vs 7.6
10.8 vs 7.8
DOR, duration of response; ITT, intention-to-treat; TPS, tumor proportion score
aAll outcomes are pembrolizumab plus pemetrexed-platinum vs placebo plus pemetrexed-platinum.
bKaplan-Meier estimate.
cPer RECIST version 1.1 by blinded independent central review.
dPFS2 was defined as the time from randomization to second/subsequent tumor progression on next-line treatment/death (per investigator assessment per RECIST version 1.1).
With ~4 years of follow-up, pembrolizumab plus pemetrexed-platinum continued to provide OS and PFS benefit vs pemetrexed-platinum alone in patients with previously untreated metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, irrespective of PD-L1 expression. Patients who received 35 cycles of pembrolizumab had durable responses and most were alive at data cutoff. Toxicity was manageable. Pembrolizumab plus pemetrexed-platinum remains a standard-of-care therapy for patients with newly diagnosed metastatic nonsquamous NSCLC.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
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: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
-
+
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): Delvys Rodríguez-Abreu
- 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
-
+
PS01 - Presidential Symposium (Japanese, Mandarin, Spanish Translation Available) (ID 143)
- Event: WCLC 2020
- Type: Plenary
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 07:00 - 09:00, Scientific Program Auditorium
-
+
PS01.09 - Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo as 1L Therapy for Metastatic NSCLC of PD-L1 TPS ≥50%: KEYNOTE-598 (ID 4248)
07:00 - 09:00 | Author(s): Delvys Rodríguez-Abreu
- Abstract
- Presentation
Introduction
In KEYNOTE-024, pembrolizumab monotherapy significantly improved survival versus platinum-doublet chemotherapy in patients with metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. We conducted the randomized, double-blind, phase 3 KEYNOTE-598 study (NCT03302234) to determine whether adding ipilimumab to pembrolizumab improved efficacy over pembrolizumab alone in this population.
Methods
Eligible patients were randomized 1:1 to ipilimumab 1 mg/kg Q6W or saline placebo for up to 18 cycles; patients in both arms received pembrolizumab 200 mg Q3W for up to 35 cycles. Randomization was stratified by ECOG PS (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). Treatment differences in the primary endpoints of OS and PFS (RECIST v1.1; blinded, independent central review) were assessed by the stratified log-rank test in the ITT population. The protocol-specified first interim analysis (IA1) was planned to occur when ~255 deaths occurred and ~12 months after the last participant was randomized. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time (RMST) between pembro–ipi and pembro–placebo of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up.
Results
Between 12‑January‑2018 and 22‑August‑2019, 568 participants were randomized to pembro–ipi (n=284; 282 treated) and pembro–placebo (n=284; 281 treated). As of 01‑September‑2020, median (range) study follow-up was 20.6 months (12.4-31.7), treatment was ongoing in 21.3% in the pembro–ipi arm vs 23.8% in the pembro–placebo arm, and median number of treatment cycles was 10 vs 15. Baseline characteristics were balanced between arms. With 272 deaths, median OS was 21.4 months for pembro–ipi vs 21.9 months for pembro–placebo (HR, 1.08 [95% CI, 0.85-1.37]; P = 0.74). RMST differences were –0.56 at the maximum observation time and –0.52 at 24 months, which met the futility criteria. With 372 events, median PFS was 8.2 months for pembro–ipi vs 8.4 months for pembro–placebo (HR, 1.06 [95% CI, 0.86-1.30]; P = 0.72). ORR was 45.4% in both arms; median DOR was 16.1 months for pembro–ipi vs 17.3 months for pembro–placebo. Treatment-related AEs occurred in 76.2% of pembro–ipi recipients vs 68.3% of pembro–placebo recipients, were of grade 3-5 in 35.1% vs 19.6%, led to death in 2.5% vs 0%, and led to discontinuation of any treatment in 25.2% vs 10.7%. Immune-mediated AEs and infusion reactions occurred in 44.7% of pembro–ipi recipients vs 32.4% of pembro–placebo recipients, were grade 3-5 in 20.2% vs 7.8%, led to death in 2.1% vs 0%, and led to discontinuation of any treatment in 14.9% vs 5.3%. Based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue ipi/placebo.
Conclusion
Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. These data confirm pembrolizumab monotherapy as a standard-of-care for this population.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
PS02 - Presidential Symposium (Re-Broadcast) (Japanese, Mandarin, Spanish Translation Available) (ID 275)
- Event: WCLC 2020
- Type: Plenary
- Track: N.A.
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 18:00 - 20:00, Scientific Program Auditorium
-
+
PS02.09 - Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo as 1L Therapy for Metastatic NSCLC of PD-L1 TPS ≥50%: KEYNOTE-598 (ID 4292)
18:00 - 20:00 | Author(s): Delvys Rodríguez-Abreu
- Abstract
Introduction
In KEYNOTE-024, pembrolizumab monotherapy significantly improved survival versus platinum-doublet chemotherapy in patients with metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. We conducted the randomized, double-blind, phase 3 KEYNOTE-598 study (NCT03302234) to determine whether adding ipilimumab to pembrolizumab improved efficacy over pembrolizumab alone in this population. Methods
Eligible patients were randomized 1:1 to ipilimumab 1 mg/kg Q6W or saline placebo for up to 18 cycles; patients in both arms received pembrolizumab 200 mg Q3W for up to 35 cycles. Randomization was stratified by ECOG PS (0 vs 1), region (East Asia vs not East Asia), and histology (squamous vs nonsquamous). Treatment differences in the primary endpoints of OS and PFS (RECIST v1.1; blinded, independent central review) were assessed by the stratified log-rank test in the ITT population. The protocol-specified first interim analysis (IA1) was planned to occur when ~255 deaths occurred and ~12 months after the last participant was randomized. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time (RMST) between pembro–ipi and pembro–placebo of ≤0.2 at the maximum observation time and ≤0.1 at 24 months of follow-up. Results
Between 12‑January‑2018 and 22‑August‑2019, 568 participants were randomized to pembro–ipi (n=284; 282 treated) and pembro–placebo (n=284; 281 treated). As of 01‑September‑2020, median (range) study follow-up was 20.6 months (12.4-31.7), treatment was ongoing in 21.3% in the pembro–ipi arm vs 23.8% in the pembro–placebo arm, and median number of treatment cycles was 10 vs 15. Baseline characteristics were balanced between arms. With 272 deaths, median OS was 21.4 months for pembro–ipi vs 21.9 months for pembro–placebo (HR, 1.08 [95% CI, 0.85-1.37]; P = 0.74). RMST differences were –0.56 at the maximum observation time and –0.52 at 24 months, which met the futility criteria. With 372 events, median PFS was 8.2 months for pembro–ipi vs 8.4 months for pembro–placebo (HR, 1.06 [95% CI, 0.86-1.30]; P = 0.72). ORR was 45.4% in both arms; median DOR was 16.1 months for pembro–ipi vs 17.3 months for pembro–placebo. Treatment-related AEs occurred in 76.2% of pembro–ipi recipients vs 68.3% of pembro–placebo recipients, were of grade 3-5 in 35.1% vs 19.6%, led to death in 2.5% vs 0%, and led to discontinuation of any treatment in 25.2% vs 10.7%. Immune-mediated AEs and infusion reactions occurred in 44.7% of pembro–ipi recipients vs 32.4% of pembro–placebo recipients, were grade 3-5 in 20.2% vs 7.8%, led to death in 2.1% vs 0%, and led to discontinuation of any treatment in 14.9% vs 5.3%. Based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue ipi/placebo. Conclusion
Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic NSCLC with PD-L1 TPS ≥50% and no targetable EGFR or ALK aberrations. These data confirm pembrolizumab monotherapy as a standard-of-care for this population.
