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Francesco Grossi
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MA10 - Considerations in Immunotherapy / Real World (ID 911)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 105
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MA10.06 - Impact of Immune-Related Adverse Events on Survival in Patients with Advanced Non-Small Cell Lung Cancer Treated with Nivolumab (ID 13039)
11:05 - 11:10 | Author(s): Francesco Grossi
- Abstract
- Presentation
Background
Anti PD1 and anti PD-L1 monoclonal antibodies represent the standard of care for platinum-pretreated advanced non-small cell lung cancer (NSCLC) patients, having shown to prolong survival compared to chemotherapy in second-line setting in phase III clinical trials. Patients treated with these drugs not infrequently experience immune-related adverse events (irAEs), which we hypothesize might reflect antitumor response. In this study we investigated whether the development of irAEs was associated with nivolumab efficacy in patients with advanced NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
We conducted a multicenter retrospective study of patients with advanced NSCLC treated with nivolumab between October 2013 and September 2017. IrAEs were defined as AEs having immunological basis that required intensive monitoring and interventions. We evaluated nivolumab efficacy according to the development of irAEs.
4c3880bb027f159e801041b1021e88e8 Result
Among 195 patients (median [range] age, 63 [30-40] years; 128 men [65.6%], 67 women [34.4%]), irAEs were observed in 85 patients (43.6%), including 15 patients (7.6%) with grade 3 or 4 events. Median PFS was 5.7 months in patients with irAEs compared to 2 months of those without irAEs (P < 0.0001). Median OS was 17.8 months compared to 4.04 months of no-irAEs group (P < 0.0001). The survival benefit of irAEs was consistent also in 12- and 6-weeks landmark analysis. Patients who developed ≥ 2 irAEs (n: 37) had a significantly longer median PFS and OS compared to those with one AE (n: 48) or none (n: 110) (PFS: 8.5 months vs. 4.6 vs. 2, P < 0.0001; OS: 26.8 months vs. 11.9 vs. 4, P < 0.0001). Multivariable analysis revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.48 (95%CI, 0.34-0.77; P < 0.0001) for PFS and 0.38 (95%CI, 0.26-0.56; P < 0.0001) for OS.
8eea62084ca7e541d918e823422bd82e Conclusion
This is the largest study conducted to date aimed to evaluate whether the development of irAEs is predictive of nivolumab efficacy in pre-treated NSCLC patients. In this study we confirmed that the development of irAEs was a strong predictor of survival outcomes in NSCLC patients who had received nivolumab in ≥ 2 line setting. This data was consistent in the 12- and 6-weeks landmark analysis, suggesting that an early onset of irAEs might be predictive of durable clinical benefit in NSCLC patients treated with nivolumab. Moreover, patients who experienced ≥ 2 irAEs had a more pronounced survival benefit compared to those with 1 irAE. Further studies are required to investigate the molecular mechanisms underlying this association.
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P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 3
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.01-53 - Bone Metastases and Efficacy of Immunotherapy in Patients with Pretreated Advanced Non-Small-Cell Lung Cancer (NSCLC) (ID 11980)
16:45 - 18:00 | Author(s): Francesco Grossi
- Abstract
Background
Approximately 40% of NSCLC patients develop bone metastases (BoM). Bone has active functions in regulating immune system. To date, no trial evaluated the role of BoM in modulating response to immunotherapy. Aim of the present study was to investigate whether presence of BoM impact on immunotherapy efficacy.
a9ded1e5ce5d75814730bb4caaf49419 Method
Two different cohorts of pretreated NSCLC patients (cohort A: Non-squamous; cohort B: Squamous) were evaluated for nivolumab efficacy in terms of objective response rate (ORR), progression free survival (PFS), and overall survival (OS) according to presence or absence of BoM. All patients received nivolumab at standard dose of 3 mg/kg every 2 weeks within the Italian Expanded Access Program.
4c3880bb027f159e801041b1021e88e8 Result
Cohort A accounted for 1588 patients with non-squamous NSCLC: 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 370 patients with squamous histology: 102 BoM+ (32%) and 251 BoM- (68%). In Cohort A, BoM+ had a significantly lower ORR (12% versus 34%; p < 0.0001), shorter PFS (2.0 versus 4.0 months, p < 0.0001) and shorter OS (7.4 versus 15.3 months, p <0.0001). In cohort B, BoM+ had significantly lower ORR (15% versus 22%; p < 0.04), shorter PFS (2.7 versus 5.4 months, p <0.0001) and shorter OS (5.0 versus 10.9 months, p <0.0001). Presence of BoM negatively affected outcome irrespective of PS (OS cohort A: PS-0 BoM+ 12.0 versus 20.9 months in PS-0 BoM-, p<0.0001; OS cohort B: PS-0 BoM+ 5.8 versus 16.4 months in PS-0 BoM-, p<0.0001). Multivariate analysis confirmed that presence of BoM independently associated with higher risk of death with HR 1.64 and HR 1.78, for Cohort A and B, respectively.
8eea62084ca7e541d918e823422bd82e Conclusion
Our results, the first assessing BoM in patients treated with immunotherapy, suggested that BoM predict lower efficacy of immunotherapy. BoM should be included as stratification factor in clinical trials.
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P1.01-73 - Preliminary Results of the SENECA (SEcond Line NintEdanib in Non-Small Cell Lung CAncer) Trial: An Italian Experience. (ID 13281)
16:45 - 18:00 | Author(s): Francesco Grossi
- Abstract
Background
Nintedanib is a multi-target small-molecule with anti-angiogenetic activity which confers longer progression free survival (PFS) and overall survival (OS) as second-line combination treatment with docetaxel versus standard-of-care, in non-squamous non-small cell lung cancer (nsNSCLC) patients, giving to rapidly progressing patients the greatest survival benefit. Considering the higher tolerability of weekly docetaxel than docetaxel q3wks in the real-life, the SENECA trial, a phase IIb, open label, Italian multicentre study, aims to evaluate whether treatment with nintedanib and docetaxel could be effective and safe as second-line option in nsNSCLC patients with the two different schedules.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients from eighteen Italian oncologic centres, with stage IIIB/IV non-oncogene addicted nsNSCLC patients, progressing after first-line chemotherapy, have been treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus continuous oral nintedanib, with the possibility of maintenance in case of stabilization or response. Primary endpoint was PFS (by investigator’s assessment), while secondary endpoints included OS, safety and quality-of-life. Study stratifies patients into two cohorts according to relapse-timing (within or over 3 months) from end of first-line chemotherapy.
4c3880bb027f159e801041b1021e88e8 Result
From January 2016 to data cut-off, on 30th March 2018, 197 patients have been evaluated: 30 were registered as screening failures, mainly for contraindications to nintedanib use. The 167 patients considered in this preliminary analysis had a median age of 63.4 years (range 35-86), were predominantly male (68.9%), smokers or former-smokers (84.4%) and with ECOG-performance status 0 (72.5%). According to investigator’s choice, 82 patients have been treated with T1 docetaxel (49.1%), 85 (50.9%) with T2 docetaxel (median docetaxel treatment 3.5 and 3.7 21-days cycles, respectively). No significant differences in median PFS have been observed between T1 and T2 (3.83 vs 4.32 months, respectively; HR 0.889 [95% IC 0.598-1.321], p-value=0.559). After a median follow-up of 7.28 months (standard deviation=5.55), a trend of similar OS has emerged in both T1 and T2 (6.63 vs 7.91 months, respectively; HR 0.770 [95% IC 0.484-1.225], p-value=0.270). Survival data of relapse-timing cohorts are not yet mature. Commonest toxicities in T1 and T2 were: fatigue (53.6% vs 65.9%, respectively), diarrhea (50.0% vs 47.0%), afebrile neutropenia (13.4% vs 52.9%) and ALT elevation (29.3% vs 20.0%).
8eea62084ca7e541d918e823422bd82e Conclusion
The SENECA trial is a real-life Italian experience, whose preliminary results confirm the efficacy and safety of second-line treatment with nintedanib and docetaxel for nsNSCLC patients, regardless from docetaxel schedule, suggesting higher toxicities for docetaxel q3wks.
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P1.01-79 - CheckMate 817: Safety of Flat-Dose Nivolumab Plus Weight-Based Ipilimumab for the First-line (1L) Treatment of Advanced NSCLC (ID 12004)
16:45 - 18:00 | Author(s): Francesco Grossi
- Abstract
Background
CheckMate 227 demonstrated significant, clinically meaningful progression-free survival benefit with 1L nivolumab 3 mg/kg every 2 weeks (Q2W) plus low-dose ipilimumab 1 mg/kg Q6W vs chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and tumor mutational burden (TMB) ≥10 mutations/megabase. The dose and schedule for this combination regimen were optimized for 1L NSCLC in CheckMate 012 and further validated in CheckMate 568 and CheckMate 227. Flat dosing of nivolumab (240 mg Q2W) may simplify treatment while providing comparable exposure, and was recently approved for previously treated NSCLC. CheckMate 817 (NCT02869789) is a multi-cohort, open-label phase 3b/4 study evaluating the safety and efficacy of flat-dose nivolumab plus weight-based low-dose ipilimumab in recurrent/metastatic NSCLC. We report safety results from Cohort A, which evaluated this regimen in the 1L setting; updated results will be presented.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with ECOG PS ≤1 and previously untreated NSCLC were eligible, regardless of tumor programmed death ligand 1 (PD-L1) expression and TMB. Nivolumab 240 mg Q2W plus ipilimumab 1 mg/kg Q6W were administered for 2 years or until disease progression/unacceptable toxicity. The primary endpoint was safety assessed by the incidence of grade ≥3 select treatment-related adverse events (TRAEs; defined as AEs of potential immunologic causes).
4c3880bb027f159e801041b1021e88e8 Result
Enrollment occurred between October 2016 and August 2017, with 391 patients initiating treatment at 68 academic and community-based centers in Europe and North America. Median age was 65 years and 27.9% of patients had squamous histology. PD-L1 expression was evaluable in 91% of patients; of these, 50% had ≥1% tumor PD-L1 expression. At database lock (March 1, 2018), minimum follow-up was 5.4 months and 34.5% of patients remained on treatment. The median (range) number of nivolumab and ipilimumab doses received were 9 (1–28) and 3 (1–10), respectively. Any grade and grade 3–4 TRAEs occurred in 74.4% and 27.6% of patients, respectively; 14.1% of patients discontinued treatment due to TRAEs. Rates of any grade select TRAEs by category ranged from 1.3% (renal) to 28.4% (skin). The most common grade 3–4 select TRAEs by category were hepatic (4.6%), pulmonary (3.1%), and gastrointestinal (3.1%). Two treatment-related deaths were reported; one due to Guillain-Barré syndrome and one due to rhabdomyolysis leading to heart failure.
8eea62084ca7e541d918e823422bd82e Conclusion
The safety profile of flat-dose nivolumab plus low-dose ipilimumab was consistent with previous reports of weight-based nivolumab plus low-dose ipilimumab optimized for NSCLC. Toxicities were manageable with no new safety signals identified.
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