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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
- Coordinates: 9/10/2019, 07:00 - 08:00, Interlaken (1988)
IBS24.01 - IO/CT First line Always (Now Available) (ID 3389)
07:00 - 08:00 | Author(s): Sonam Puri
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.
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
Cross over allowed
Pembrolizumab + Carboplatin/Cisplatin + pemetrexed vs placebo+ carboplatin/cisplatin+ pemetrexed
22.0 m vs 10.7 m
(HR 0.56, 95% CI 0.45-0.70), p < .00001
(HR 0.48, 95% CI 0.40-0.58, p < .00001)
Arm 1: Atezolizumab, carboplatin, paclitaxel and bevacizumab (ABCP)
Arm 2: Atezolizumab, carboplatin, paclitaxel (ACP)
Arm 3: Carboplatin, paclitaxel and bevacizumab (BCP)
Arm 1 vs. Arm 3
ABCP vs BCP
19.2m vs 14.7m
(HR:0.78, 95%CI 0.64-0.96) p=0.02
8.3m vs 6.8m
(HR:062, 95%CI 0.52-0.74), p<0.001
Atezolizumab+ carboplatin +nab paclitaxel vs. carboplatin+ nab paclitaxel
18.6m vs. 13.9m (HR:0.79 95% CI 0.64-0.98), p=0.033
7m vs 5.5m (HR:0.64, 95%CI 0.54-0.77), p<0.0001
Pembrolizumab + carboplatin+(nab) paclitaxel vs. Placebo + carboplatin+(nab) paclitaxel
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
Atezolizumab+ carboplatin+ (nab) paclitaxel vs. carboplatin+ (nab) paclitaxel
14.9m vs 13.9m (HR=0.96, 95%CI 0.78-1.18), p=0.69
6.3m vs 5.6m (HR=0.71, 95% CI 0.60-0.85), p=0.0001
Arm 1: Nivolumab + ipilimumab
Arm 2: Nivolumab + platinum doublet chemotherapy
Arm 3: platinum doublet chemotherapy
Arm 2 vs Arm 3
5.6m vs 4.7m (HR:0.74 95%CI 0.58-0.94)
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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
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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 | Author(s): Sonam Puri
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.