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Jhanelle Elaine Gray
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IBS24 - Optimal Immunotherapy Sequence in Stage IV NSCLC (Ticketed Session) (ID 55)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/10/2019, 07:00 - 08:00, Interlaken (1988)
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IBS24.01 - IO/CT First line Always (Now Available) (ID 3389)
07:00 - 08:00 | Presenting Author(s): Jhanelle Elaine Gray
- Abstract
- Presentation
Abstract
Combination therapy with anti-programed death protein (ligand) 1 inhibitor (PD-1/PD-L1) and platinum-doublet chemotherapy (CT) plus/minus vascular endothelial growth factor inhibition (VEGFi) has recently emerged as the standard first-line treatment for patients with metastatic non-small cell lung cancer (mNSCLC) without a targetable oncogene. The rationale for using the immunotherapy chemotherapy (IO-CT) combination comes primarily from a clinical effort to improve the efficacy of the first-line treatment of mNSCLC by combining two independently active therapies with non-overlapping toxicity profiles. Additional proof-of-principle comes from pre-clinical studies showing synergy between checkpoint inhibitors (CPIs) and CT through platinum mediated immunomodulation of the tumor microenvironment.1, 2
Several randomized phase II-III clinical trials have evaluated the combination of platinum doublet CT with CPIs for first line therapy of mNSCLC (Table 1). Pembrolizumab (anti-PD-1) plus platinum-pemetrexed was the first IO-CT combination with promising activity in this setting as noted in the phase II KEYNOTE021 trial.3 This led to further evaluation of the combination in the phase III KEYNOTE189 trial 4 that compared platinum-pemetrexed with pembrolizumab or placebo in treatment naïve patients with non-squamous mNSCLC .The results showed a significant overall survival (OS) benefit with the pembrolizumab combination that was seen irrespective of the PD-L1 tumor proportion score (TPS) and persisted at the updated follow up analysis despite cross over to IO in 54% patients in the placebo-CT arm.5 Similarly, the KEYNOTE407 trial enrolled untreated patients with stage IV squamous NSCLC, and noted superior outcomes with the combination of pembrolizumab plus carboplatin-(nab) paclitaxel versus placebo-carboplatin-(nab)paclitaxel.6 These two trials have established pembrolizumab plus platinum CT as the preferred therapy for previously untreated patients with non-squamous and squamous mNSCLC, and both regimens are currently approved by the FDA for histology specific, front-line treatment of stage IV NSCLC. Additional trials have been conducted comparing the combination of atezolizumab (anti-PD-L1) plus platinum- (nab)paclitaxel versus placebo-CT for the first-line treatment of non-squamous (IMpower 130, IMpower150) and squamous (IMpower131) mNSCLC. While results of the IMpower130 study show an OS benefit of treatment with the atezolizumab-CT combination compared to CT alone 7, the IMpower131 trial showed a clear PFS benefit but no significant benefit in OS between the two arms.8 Interestingly, the potential benefit of adding VEGFi to IO-CT was explored in the IMpower150 trial. This complex, three arm trial compared the combination of atezolizumab, carboplatin, paclitaxel and bevacizumab (ABCP) and atezolizumab, carboplatin, paclitaxel (ACP) to carboplatin, paclitaxel and bevacizumab (BCP) in CT naïve, non-squamous, mNSCLC. The trial also enrolled a subset of patients with EGFR or ALK mutations who had failed standard tyrosine kinase therapies, a population of patients that historically have a poor response to treatment with CPIs and are otherwise excluded from majority of the IO or IO-CT combination trials. The results showed a survival benefit of the four-drug regimen (ABCP vs BCP) in both the EGFR/ALK WT and mutated population, highlighting the potential role of VEGFi in improving response to CPIs, especially in oncogene driven mNSCLC.9
Coming back to the question “should IO-CT be first line always?” The answer is yes, for the majority of eligible mNSCLC patients with no targetable mutations. mNSCLC is an aggressive malignancy associated with high mortality, and multiple trials have shown that many patients do not have the opportunity of receiving 2nd line treatment.5,10 Platinum based CT has been the first-line treatment of choice for mNSCLC for many years. In the last decade, IO has revolutionized the treatment of advanced lung cancer. Recent data (Table 1) clearly demonstrates superior and durable clinical outcomes with the combination of platinum-based CT doublets and CPIs compared to CT alone in both squamous and non-squamous mNSCLC. These combinations are safe with little additive toxicity and should be adopted as routine standard of care therapies in the frontline setting, especially in high disease burden and PD-L1 TPS ≤1. However, there is variability in outcomes based on histological subtypes of mNSCLC and the different IO-CT combinations (Table 1). New trial design strategies are needed to determine the benefit of IO-CT versus IO alone, especially in patients with borderline performance status or PD-L1 TPS ≥50%. Additionally, it is also important to determine the subgroup of patients with the highest likelihood of benefit from addition of VEGFi to IO-CT.
References
1.Galluzzi L et al. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28(6):690-714.
2. Pfirschke C, Engblom C, Rickelt S, et al. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity. 2016;44(2):343-354.
3. Langer CJ et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous NSCLC: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508.
4. Gandhi L et al. Pembrolizumab plus Chemotherapy in Metastatic NSCLC. NEJM. 2018;378(22):2078-2092.
5. Gadgeel S et al. JCO 2019, 37. (suppl; abstr 9013).
6. Paz-Ares L et al. Pembrolizumab plus Chemotherapy for Squamous NSCLC. NEJM. 2018;379(21):2040-2051.
7. West H et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic NSCLC(IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019.
8. Jotte R et al. IMpower 131. JCO 2018, 36. (suppl;abstr LBA900)
9. Socinski MA et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. NEJM. 2018;378(24):2288-2301.
10. Reck M et al. Pembrolizumab vs. Chemotherapy for PD-L1-Positive NSCLC. NEJM. 2016;375(19):1823-1833.
Table 1: Summary of key phase III first line IO-CT trials in mNSCLC
Trial name
Histology
Treatment
Cross over allowed
Results
KEYNOTE189
Non squamous
Pembrolizumab + Carboplatin/Cisplatin + pemetrexed vs placebo+ carboplatin/cisplatin+ pemetrexed
Yes
OS
22.0 m vs 10.7 m
(HR 0.56, 95% CI 0.45-0.70), p < .00001
PFS
(HR 0.48, 95% CI 0.40-0.58, p < .00001)
IMpower150
Non squamous
Arm 1: Atezolizumab, carboplatin, paclitaxel and bevacizumab (ABCP)
Arm 2: Atezolizumab, carboplatin, paclitaxel (ACP)
Arm 3: Carboplatin, paclitaxel and bevacizumab (BCP)
No
Arm 1 vs. Arm 3
ABCP vs BCP
OS
19.2m vs 14.7m
(HR:0.78, 95%CI 0.64-0.96) p=0.02
PFS
8.3m vs 6.8m
(HR:062, 95%CI 0.52-0.74), p<0.001
IMpower130
Non squamous
Atezolizumab+ carboplatin +nab paclitaxel vs. carboplatin+ nab paclitaxel
Yes
OS
18.6m vs. 13.9m (HR:0.79 95% CI 0.64-0.98), p=0.033
PFS
7m vs 5.5m (HR:0.64, 95%CI 0.54-0.77), p<0.0001
KEYNOTE407
Squamous
Pembrolizumab + carboplatin+(nab) paclitaxel vs. Placebo + carboplatin+(nab) paclitaxel
Yes
OS:
15.9m vs.11.3m (HR:0.64, 95% CI:049-0.85), p<0.001
PFS: 6.4mvs.4.8m (HR:0.56, 95% CI:045-0.70), p<0.001
IMpower131
Squamous
Atezolizumab+ carboplatin+ (nab) paclitaxel vs. carboplatin+ (nab) paclitaxel
No
OS
14.9m vs 13.9m (HR=0.96, 95%CI 0.78-1.18), p=0.69
PFS
6.3m vs 5.6m (HR=0.71, 95% CI 0.60-0.85), p=0.0001
Checkmate227
Both
Arm 1: Nivolumab + ipilimumab
Arm 2: Nivolumab + platinum doublet chemotherapy
Arm 3: platinum doublet chemotherapy
NA
Arm 2 vs Arm 3
PFS
5.6m vs 4.7m (HR:0.74 95%CI 0.58-0.94)
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-09 - Predictive Clinical and Molecular Features of Long-Term Survivors Receiving Immune Checkpoint Inhibitors for Stage 4 Non-Small Cell Lung Cancer (Now Available) (ID 857)
09:45 - 18:00 | Author(s): Jhanelle Elaine Gray
- Abstract
Background
We hypothesized that clinical features could predict for durable response in patients treated immune checkpoint inhibitors (ICI). We performed an exploratory retrospective analysis with the primary endpoint of determining features associated with long-term survival.
Method
We identified 212 consecutive patients with stage 4 NSCLC who received PD-1-ICI on clinical trials between 2011-2015. Overall survival (OS) was estimated by Kaplan–Meier; multivariate analyses were performed using Cox regression.
Result
Baseline Characteristics: median age 67, 52% male, 69% non-squamous, median 31 pack-years-smoking, 63% chemotherapy-naïve, 31% KRAS-mutant, 11% PIK3CA-mutant. At a 57-month minimum follow-up, median OS was 12.2 mo (95%CI 10.2-14.2). Attaining PR/CR was associated with long-term survival (HR 0.21, p < 0.001). Long-term (>4-yr) survivors were more likely non-squamous histology, PIK3CA-wild-type, and low baseline neutrophil-to-lymphocyte proportion (Figure_1). Patients who received dual PD-1/CTLA-4-ICI (39%) had improvements in ORR (43% vs. 23%), time-to-progression (TTP, p = 0.001) and OS (HR 0.63, p = 0.006) versus PD-1 alone.
In 38 long-term (OS range 48-86 months) survivors (Figure_2), 26% received local ablative therapy without any further systemic therapy and successfully maintained durable remissions. There was no difference in ORR or OS for the 34% who discontinued ICI early due to toxicity.
Conclusion
Objective responses to ICI with subsequent oligoprogression may be effectively salvaged with local ablative therapy in select cases. Prospective validation of surrogate biomarkers of immune response remain of paramount importance. Furthermore, durable responses exceeding 5 years may be attained despite early cessation of ICI. The role and clinical significance of PIK3CA mutations and ICI-resistance requires further investigation.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-06 - Phase I Study of Nivolumab and Ipilimumab Combined with Nintedanib in Advanced Non-Small Cell Lung Cancer (ID 2000)
10:15 - 18:15 | Presenting Author(s): Jhanelle Elaine Gray
- Abstract
Background
Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) inhibit tumor infiltrating lymphocyte activation and are potentially immunosuppressive. Targeting the TME may represent an important synergistic approach in immunotherapy (IO). Combination IO with nivolumab and ipilimumab has proven clinical activity in NSCLC. Nintedanib is an orally available triple kinase inhibitor that is active against NSCLC, inhibits CAFs, and targets VEGFR, FGFR and PDGFR. We report the preliminary results of a phase 1 dose escalation trial evaluating the combination of nintedanib with nivolumab and ipilimumab (N+N+I) in advanced NSCLC pts.
Method
This is single center, investigational, non-randomized trial of IO naïve or IO pretreated pts with locally advanced or metastatic NSCLC. Primary endpoint is to determine the safety and tolerability of concurrent administration of the proposed regimen. Key secondary endpoints include RR, DOR, OS, PFS. Five dose levels of nintedanib (dose level -1, 0, 1, 2 and 3 with nintedanib given at dose 100 mg once daily,150 mg once daily and 100mg, 150 mg and 200 mg twice daily respectively) are given with fixed dose of nivolumab (3mg/kg every 2 weeks) and ipilimumab (1mg/kg every 6 weeks). Dose escalation was achieved by the 3+3 design. Blood and tumor biopsies are obtained to evaluate potential predictive and resistance mechanisms.
Result
Enrollment to phase I dose escalation was started on 29th January 2018 and to date 13 patients have been treated on dose level -1 (3), 0 (5) and 1(5). 54% (7) were IO pretreated and 46% (6) were IO naive. Median age is 65 with 62% (8) female patients, ECOG 1 62% (8) and 15% (2) never smoker/ 85% (11) prior or current smokers. Most common AE of any grade were transaminitis and rash in 23% (3). Most G3 AE was transaminitis 8% (1). There were no G4/5 AEs or DLTs. There was no treatment discontinuation due to AEs. PD-L1 expression was < or = 1% in 46% (6), 1-49% in 8% (1) and >/= 50% in 46% (6) pts. Amongst the 12 patients evaluable for confirmed response, 17% (2) had PR, 50% (6) had SD and 33% (4) had PD. In the IO pretreated group, 14% (1) had PR, 57% (4) had SD and 28% (2) had PD.
Conclusion
The combination of N+N+I was well tolerated. The regimen demonstrates antitumor activity despite progression on prior IO. The updated and mature data of the phase I dose escalation trial will be presented at the meeting. Clinical trial information: NCT03377023.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-45 - A Phase 1b Dose-Escalation Study of Carotuximab in Combination with Nivolumab in Patients with Metastatic NSCLC (Now Available) (ID 926)
10:15 - 18:15 | Author(s): Jhanelle Elaine Gray
- Abstract
Background
Nivolumab has demostrated clinical benefit in advanced non-small cell lung cancer (NSCLC) patients who have progressed following platinum-based chemotherapy.Carotuximab (TRC105) is an antibody to endoglin, a receptor expressed on proliferating endothelial cells and myeloid derived suppressor cell (MDSCs), which potently complements the activity of antibody targeting the programmed death receptor (PD-1) in preclinical models. By targeting MDSCs, carotuximab has the potential to complement nivolumab in patients with refractory metastatic NSCLC.
Method
Patients with refractory metastatic NSCLC were enrolled regardless of baseline PD-L1 tumor expression and treated with 8 mg/kg or 10 mg/kg of carotuximab weekly for four doses and then 15 mg/kg every two weeks, in combination with the approved dose of nivolumab of 240 mg every two weeks using a standard "3+3" dose escalation design. Expansion cohorts were then opened to further assess the safety, tolerability, and preliminary efficacy by iRECIST of the recommended Phase 2 dose (RP2D) of carotuximab with standard dose nivolumab.
Result
The combination of carotuximab and nivolumab was well-tolerated without dose limiting toxicitiy in 6 patients treated as part of dose escalation. One of these 6 patients, whose archival tumor did not express PD-L1 and who had not received prior PD-1/PD-L1 checkpoint inhibition treatment, developed a partial response and remains on study after 14 months. Two of the other 5 patients, one of whom who progressed following prior nivolumab treatment, achieved stable disease, one of whom remains on study at 7 months.. Common adverse events regardless of relationship included low grade headache, vomiting, anemia, dyspnea, fatigue, cutaneous telangectasia, nausea, bleeding gums, diarrhea, and migraine. Target concentrations of carotuximab were achieved in all patients and anti-drug antibody was not detected. Enrollment is continuing in two parallel 12 patient expansion cohorts, one in patients who relapsed following prior PD-1/PD-L1 checkpoint inhibition and one in patients naive to PD-1/PD-L1 checkpoint inhibition.
Conclusion
Carotuximab at its RP2D of 10 mg/kg weekly x 4 and then 15 mg/kg every 2 weeks was tolerable with nivolumab in patients with NSCLC, and demonstrated preliminary signs of efficacy
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-24 - An Open-Label Randomized Phase II Study of Combining Osimertinib With and Without Ramucirumab in TKI-Naïve EGFR-Mutant Metastatic NSCLC (ID 851)
10:15 - 18:15 | Author(s): Jhanelle Elaine Gray
- Abstract
Background
Osimertinib, a third-generation EGFR inhibitor, has become the first-line therapy for patients with metastatic EGFR-mutant NSCLCs since 2018. Osimertinib is well-tolerated, therefore, it opens opportunities to be combined with other therapeutic agents to enhance the treatment outcome. In preclinical models, it has been shown that upregulated VEGF signaling mediates acquired resistance to EGFR therapies. In xenograft models, combination of anti-VEGF medications with EGFR inhibitors were significantly more effective than erlotinib or gefitinib alone. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, is approved with docetaxel in as second line treatment for NSCLCs. In clinical trial evaluations, the phase 3 RELAY trial (NCT02411448) studying ramucirumab plus erlotinib in patients with metastatic untreated EGFR-mutant NSCLC patients showed a statistically significant improvement in progression-free survival in the combination group compared to erlotinib alone. A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With strong preclinical and clinical evidence showing dual inhibition of VEGF/EGFR signaling prolongs progression-free survival for EGFR-mutant lung cancers, and demonstrated safety, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination’s efficacy in treatment-naïve EGFR-mutant NSCLC.
Method
The OSI+RAM trial is a randomized phase 2 study with the primary endpoint being progression-free survival in osi+ram group as compared to osimertinib monotherapy group. The major inclusion criteria include patients with metastatic NSCLC harboring EGFR mutations (L858R/Exon 19 del). The major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. Based on the results from erlotinib bevacizumab (NEJ026) study, we expect an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65. The trial plans to enroll total of 150 patients, with 100 allocating to osi+ram arm and 50 to osimertinib monotherapy. Total of 9 study sites in the USA are planned. Hoosier Cancer Research Network will facilitate the execution of the trial. The trial protocol has received IND exemption from US FDA and has been approved by IRB at MD Anderson Cancer Center. The first subject is expected to be enrolled in May 2019. A planned interim analysis will be performed after the first 75 subjects are enrolled. NCT03909334.
Result
Section not applicable
Conclusion
Section not applicable
