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Naiyer Rizvi
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ES02 - Pro-Con: Do We Need Biomarkers to Guide the Choice of Immunotherapy Treatment? (ID 157)
- Event: WCLC 2020
- Type: Educational Session
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 10:30 - 11:30, Scientific Program Auditorium
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ES02.02 - Immune Checkpoint Blockade for All NSCLC Regardless of PD-L1, TMB or Other Biomarkers (ID 3971)
10:30 - 11:30 | Presenting Author(s): Naiyer Rizvi
- Abstract
- Presentation
Abstract not provided
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OA01 - Established Drugs in Special Populations and New Drugs in Established Populations (ID 226)
- Event: WCLC 2020
- Type: Oral
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 09:15 - 10:15, Scientific Program Auditorium
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OA01.03 - Clinical Benefits of First-Line (1L) Cemiplimab Monotherapy by PD-L1 Expression Levels in Patients With Advanced NSCLC (ID 3035)
09:15 - 10:15 | Author(s): Naiyer Rizvi
- Abstract
- Presentation
Introduction
Despite approval of programmed cell death (PD)-1 inhibitor monotherapy as 1L treatment for advanced non-small cell lung cancer (NSCLC), the clinical significance of PD-ligand 1 (PD-L1) expression levels above the 50% threshold remains unclear.
Methods
EMPOWER-Lung 1 is a randomized, open-label, Phase 3 study of anti–PD-1 cemiplimab 350 mg every 3 weeks, versus platinum doublet chemotherapy, as 1L treatment in patients with advanced NSCLC and PD-L1 ≥50% (NCT03088540). This exploratory post-hoc analysis assesses the clinical benefits of study treatment by PD-L1 expression tertiles in a randomized sub-population (n=475) with PD-L1 ≥50% by 22C3 assay. Data cut-off was March 1, 2020.
Results
In the cemiplimab arm (n=238), 33.6%, 31.9%, and 34.5% of patients had PD-L1 ≥90%, >60% to <90%, and ≥50% to ≤60%, respectively; corresponding proportions in the chemotherapy arm (n=237) were 34.2%, 30.4%, and 35.4%, respectively. Overall, cemiplimab provided significantly better OS, PFS, and objective response rate (ORR) than chemotherapy, with incremental benefits by increasing PD‑L1 expression seen with cemiplimab, but not chemotherapy (Table). The largest difference in ORR between cemiplimab (38.8% [95% CI: 28.1–50.3]) and chemotherapy (14.8% [95% CI: 7.9–24.4]) was observed in patients with PD-L1 ≥90%. Depth of tumor size reduction was greater with cemiplimab than that of chemotherapy and correlated with PD-L1 levels (Figure). Median DOR has not been reached with cemiplimab (95% CI: 10.5–not evaluable) versus chemotherapy (6-months [95% CI: 4.3–8.3]). Kaplan–Meier estimated DOR >12 months was higher with cemiplimab (67.7% [95% CI: 45.7–82.3]) compared to chemotherapy (15.0% [95% CI: 1.5–42.6]).
Conclusion
Overall, the benefit (OS, PFS, and ORR) with cemiplimab was superior to chemotherapy, and incrementally associated with PD-L1 expression levels. Thus, baseline PD-L1 expression levels may be used to identify patients with advanced NSCLC who are most likely to derive greatest benefit from 1L cemiplimab monotherapy.
Table. Correlation of survival and objective response rate with baseline PD-L1 levels Overall survival Progression-free survival Tumor response Median, months
(95% CI)HR (95% CI) Median, months
(95% CI)HR (95% CI) ORR, % (95% CI) Overall NR (NE–NE)
vs.
12.1 (10.2–17.5)0.57
(0.40–0.80)6.3 (4.5–8.5)
vs.
5.6 (4.3–6.2)0.60
(0.47–0.77)35.3 (29.2–41.7)
vs.
17.7 (13.1–23.2)By PD-L1 expression tertile PD-L1 ≥90% NR (13.4–NE)
vs.
13.3 (10.2–NE)0.54
(0.27–1.10)12.7 (9.8–13.4)
vs.
6.1 (4.2–6.2)0.33
(0.19–0.58)38.8 (28.1–50.3)
vs.
14.8 (7.9–24.4)PD-L1 >60 to <90% NR (NE–NE)
vs.
14.2 (9.6–17.5)0.49
(0.26–0.92)6.2 (4.2–8.4)
vs.
4.3 (4.1–5.9)0.57
(0.38–0.85)39.5 (28.4–51.4)
vs.
16.7 (8.9–27.3)PD-L1 ≥50 to ≤60% NR (13.2–NE)
vs.
11.7 (8.3–NE)0.74
(0.44–1.24)4.3 (2.8–5.2)
vs.
6.0 (4.4–6.2)0.89
(0.61–1.29)28.0 (18.7–39.1)
vs.
21.4 (13.2–31.7)Median survival, and ORR data are shown for cemiplimab versus chemotherapy, respectively. ORR defined as the proportion of patients with a best overall response of confirmed complete or partial response. PFS in the PD-L1 ≥50 to ≤60% subgroup has the widest CIs which makes the PFS estimate HR highly unstable.
CI, confidence interval; HR, hazard ratio; NE, not evaluable; NR, not reached; ORR, objective response rate; PD-L1, programmed cell death-ligand 1; PFS, progression free survival.
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OA07 - Immuno-biology and Novel Immunotherapeutics from Bench to Bed (ID 228)
- Event: WCLC 2020
- Type: Oral
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 10:30 - 11:30, Scientific Program Auditorium
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OA07.08 - HUDSON: An Open-Label, Multi-Drug, Biomarker-Directed, Phase II Platform Study in Patients with NSCLC, who Progressed on Anti-PD(L)1 Therapy (ID 3535)
10:30 - 11:30 | Author(s): Naiyer Rizvi
- Abstract
- Presentation
Introduction
The HUDSON Platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. The study design allows efficacy, safety, and tolerability assessment of multiple tailored durvalumab based combinations. Novel treatment options for this population can be explored based on efficacy signals. Here we present initial results in Modules 1, 2, 3 and 5 and current status in Modules 6 and 7.
Methods
Patients are enrolled into cohorts defined according to a biomarker matched profile (Part A) or non-matched (Part B). Acquired resistance (ACQ) was defined as progression after >24 weeks of prior immunotherapy and primary resistance (PRI) defined as progression ≤24 weeks from onset of prior immunotherapy. Patients received durvalumab in combination with: olaparib (PARPi; Module 1), danvatirsen (STAT3i; Module 2), ceralasertib (ATRi; Module 3), oleclumab (anti-CD73 antibody; Module 5), trastuzumab deruxtecan (HER2 ADC; Module 6), and cediranib (VEGFRi; Module 7). A composite endpoint of overall response rate (ORR), progression-free survival (PFS; 6, 9 and 12 months) and overall survival (OS; 6, 9 and 12 months) was used to decide whether or not to expand the initial module size from 20 patients to 40. Safety, a secondary endpoint, was continuously monitored.
Results
Enrolment started in December 2017. As of 25th July 2020, 261 patients have been enrolled from 31 study sites in 6 countries. Enrolment into Modules 1, 2, and 5 is complete, ongoing in Modules 3, 6, and 7, and Module 4 was discontinued with one patient enrolled, when development of vistusertib was stopped. As of Q1 2020, efficacy (ORR), PFS and OS) results were available as per Table 1. Further efficacy updates for Modules 1, 2, 3 and 5 are scheduled in Q3 2020. The safety profile of combination therapy in each module was in line with the safety profile of the individual compounds.
Table 1. Enrolment and efficacy outcomes to date per patient cohort
Cohort
Enrolment status
Number
enrolled6-month OS (%)
6-month PFS (%)
ORR
(%)Median total
treatment duration (months)
Part A – Biomarker matched
LKB1 (+olaparib)
Complete
21
55.8
10.7
4.8
1.84
HRR (+olaparib)
Complete
21
57.1
21.8
4.8
3.68
ATM (+ceralasertib)
Ongoing
18
100
61.2
13.3
4.14
CD73 (+oleclumab)
Complete
23
79.9
8.3
0
2.79
HER2 (+trastuzumab deruxtecan)
Ongoing
1
–
–
–
–
Part B – Biomarker non-matched
PARPi – ACQ
(+olaparib)Complete
23
77.4
26.1
4.3
4.70
PARPi – PRI (+olaparib)
Complete
22
59.1
15.1
0
3.35
STAT3i – ACQ
(+danvatirsen)
Complete
22
75.2
38.5
0
3.15
STAT3i – PRI (+danvatirsen)
Complete
23
50.2
5.1
0
1.91
ATRi – ACQ (+ceralasertib)
Complete
24
77.3
37.0
8.7
6.44
ATRi – PRI (+ceralasertib)
Complete
20
74.8
53.8
11.1
2.78
CD73 Ab – ACQ
(+oleclumab)Complete
25
64.4
26.1
0
2.73
CD73 Ab – PRI (+oleclumab)
Complete
9
NC
NC
0
1.53
VEGFi – ACQ
(+cediranib)Ongoing
9
–
–
–
NA
Please note: OS, PFS and ORR are currently available for patients enrolled by January 2020. Number enrolled reflects the total enrolled by 25th July 2020.
Conclusion
Preliminary efficacy signals were observed with ATRi, which may be more pronounced in ATM selected patients. The subgroup of LKB1 selected patients appear to have the lowest 6-month OS and PFS of subgroups in Module 1 (durvalumab + olaparib). An update is scheduled for Q3 2020.
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P16 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Translational) (ID 155)
- 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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P16.07 - Immuno-Modulatory Effects of Ceralasertib in Combination with Durvalumab in NSCLC with Progression on Anti-PD(L)1 Treatment (HUDSON) (ID 3491)
00:00 - 00:00 | Author(s): Naiyer Rizvi
- Abstract
Introduction
The HUDSON platform trial (NCT03334617) is a multi-arm clinical trial for patients with non-small cell lung cancer (NSCLC) who had tumour progression on anti-PD(L)1 immunotherapy and received prior platinum-doublet chemotherapy. We report preliminary translational data, where available, from patients treated with ceralasertib (an ataxia telangiectasia and Rad3-related protein inhibitor, ATRi) and the PDL1 inhibitor durvalumab.
Methods
The study protocol included analyses of archival and fresh tumour biopsies, and longitudinal liquid biopsies. Patients were enrolled into biomarker matched (ATM-selected) or unmatched arms after the development of primary or acquired resistance to PD-(L)1 immunotherapy. Primary and acquired resistance were defined as progression before or after 6 months on anti-PD(L)1 therapy respectively. Biomarker status was determined using next generation sequencing (Foundation Medicine) for ATM mutation status or immunohistochemistry (IHC, Ventana) for ATM protein expression. Gene expression from whole blood samples (PAXgene®) was analysed using the PanCancer IO gene panel from Nanostring Technologies.
Results
Translational data are currently only available from a subset of patients. Clinical response data will be presented separately. Tumour and liquid biopsy samples were collected from patients treated with ceralasertib and durvalumab. Gene expression data were available from 8 ATM biomarker-positive and 17 biomarker-negative patients. Peripheral gene expression analyses in responding patients showed greater than two-fold higher granzyme levels at baseline, when compared with non-responders. The 19 patients with controlled disease on ceralasertib (partial response or stable disease by RECIST v1.1) and available gene expression data also showed a two-fold reduction in peripheral IL-8 gene expression in paired blood samples when compared with the six patients showing progressive disease with available gene expression data. Samples collected during a ceralasertib-only period prior to durvalumab treatment showed modified biomarkers of peripheral immunity including significant increases in antigen presentation gene signature and significant decreases in both exhausted T cell and NK cell signatures from bulk whole-blood RNA samples. Ceralasertib also decreased 4 macrophage gene expression signatures in on-treatment samples. Similar gene expression profiles were not observed from comparable samples on other HUDSON arms. No correlation between ATM biomarker status and RECIST response was observed. No significant correlations with ceralasertib response were observed between tumour mutation burden or PDL1 status by IHC.
Conclusion
Taken together, these data support a role of immune activation by ceralasertib as a feature of response to combination therapy with ceralasertib plus durvalumab in NSCLC following progression on anti-PD(L)1.
