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Massimo Di Maio
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OA07 - Precision Medicine Involves Biology and Patients (ID 132)
- Event: WCLC 2019
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Silvia Novello, Fabrice Barlesi
- Coordinates: 9/09/2019, 11:00 - 12:30, Copenhagen (1980)
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OA07.07 - Quality of Life (QoL) Analysis in Lung Cancer: A Systematic Review of Phase III Trials Published Between 2012 and 2018 (Now Available) (ID 1958)
11:00 - 12:30 | Author(s): Massimo Di Maio
- Abstract
- Presentation
Background
We previously reported that QoL is not included among endpoints and QoL results are underreported in a high proportion of phase III trials in oncology. Here we describe QoL prevalence and heterogeneity in QoL reporting in lung cancer phase III trials.
Method
We selected all primary publications of lung cancer phase III trials evaluating anticancer drugs published between 2012 and 2018 by 11 major journals. We analyzed QoL inclusion among endpoints, presence of QoL results and methodology of QoL analysis.
Result
122 publications were identified. In 39 (32.0%) publications, QoL was not listed among endpoints: 10/17 (58.8%) early stage/locally advanced NSCLC, 15/54 (27.8%) first-line of advanced NSCLC; 10/41 (24.4%) second and further lines of advanced NSCLC, 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012-2015 vs. 30.6% in 2016-2018. QoL was not listed among endpoints in primary publication in 16/80 (20.0%) for-profit trials vs. 23/42 (54.8%) no-profit trials. Out of 83 trials including QoL among endpoints, QoL results were not reported in 36 primary publications (43.4%). Proportion of trials not reporting QoL results in primary publication significantly increased over time (30.6% 2012-2015 vs. 61.8% 2016-2018, p=0.005). Overall, QoL data were not available in 65/122 (61.5%) primary publications, due to the absence as endpoint or unpublished results. QoL data were not available in primary publication in 48/80 (60.0%) for-profit trials vs. 27/42 (64.3%) no-profit trials. QoL data were lacking in 48/78 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement in time to publication comparing 2012-2015 vs. 2016-2018. Out of 83 trials including QoL, most common tools were EORTC QLQ-C30 (42, 50.6%); EORTC LC13 (39, 47.0%); EQ-5D (37, 44.6%); LCSS (19, 22.9%); FACT-L (15, 18.1%). Out of 58 trials with available results, common methods of analysis were mean scores or changes (45, 77.6%), time to deterioration (31, 53.4%) and proportion of responders (19, 32.8%). Availability of a secondary QoL publication allowed a higher number of methods of QoL analysis (p<0.001).
Conclusion
QoL is not assessed in a high proportion of phase III trials evaluating lung cancer patients, a setting where attention to QoL should be particularly high, due to symptoms and limited life expectancy. Furthermore, the timely inclusion of QoL results in primary publications is worsening in recent years. Secondary publications allow a more complete description of QoL results, but imply a delay in their availability.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-26 - ALK Fusion Variant Detection by Targeted RNA-Seq in TKIs Treated ALK-Positive Lung Adenocarcinoma (ID 1860)
09:45 - 18:00 | Author(s): Massimo Di Maio
- Abstract
Background
Clinical outcomes of ALK positive (ALK+) Non-Small-Cell Lung Cancer (NSCLC) and the identification of the most effective anaplastic lymphoma kinase inhibitor (ALKi) according to the specific ALK fusion variants are not well assessed. We retrospectively characterized fusion variant distribution in a cohort of ALK+ lung adenocarcinomas (ADC) with paired clinical data about treatments and outcomes.
Method
Diagnostic tumor tissue from advanced ALK+ (by FISH and/or IHC) ADC diagnosed from 2010 to 2018 and treated with single or multiple ALKis were collected (expanded cohort from Gobbini et al. Lung Cancer, 2017). The OncomineTM Solid Tumor Fusion Transcript Kit on an Ion PGM™ system and the Ion Reporter™ software were used to identify targeted ALK fusion gene products (ThermoFisher).
Result
Specific fusion variant transcripts were found in 34/55 (62%) of collected samples. As expected, EML4-ALK fusion transcripts were the most common (31/34 samples, 91%), but HIP-ALK transcripts were also detected (3/34 - 9%). Among EML4-ALK fusions the following variants were detected: V1 (n=11); V2 (n=2); V3a/b (n=12 ) V5a/b (n=5 ) and E6A19 (n=1). Patient median age was 60 year [range 36-85], 22 were male and 12 female. Three patients were current, 11 former and 20 never smokers. Crizotinib, alectinib, ceritinib, brigatinib and lorlatinib were the ALKis used. Independently of the therapy line, 12 patients received crizotinib only, while 22 patients received crizotinib followed by one or two other ALKis. Regardless of the type of transcript, those patients who received more than one ALKi had a better median overall survival compared to those receiving crizotinib only, as expected (74 vs 21 months, HR: 5.31; 95%CI: 1.464-19.26, log rank p=0.0006). Furthermore, a significant difference in the mean duration of the different ALKi treatment was found according to the ALK variants (Chi-square p<0.0001), suggesting a private ALKi efficacy profile for specific fusion variants. Finally, the 3 HIP-ALK cases showed a better outcome with respect the EML4-ALK variants (not reached vs 51 months).
Conclusion
Our analysis suggests that different ALK fusion variant might affect ALKi treatment duration in ALK+ lung ADC.
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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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P2.04-15 - Association Between Opioids and Outcome of 1st Line Immunotherapy in Advanced NSCLC Patients: A Retrospective Evaluation (Now Available) (ID 2428)
10:15 - 18:15 | Author(s): Massimo Di Maio
- Abstract
Background
Opioids represent the pharmacological backbone of cancer-related pain treatment. However, preclinical studies suggest that opioids can cause immunosuppression. Recently, immune checkpoint inhibitors (ICIs) have become available for treatment of patients with advanced NSCLC. With this study we aimed at retrospectively evaluate the impact of chronic opioid treatment on the outcome of advanced NSCLC (aNSCLC) patients treated with first-line ICIs.
Method
We retrospectively reviewed the records of aNSCLC patients treated with anti-programmed-death-1 (PD-1) or its ligand (PD-L1) single-agent ICIs in 2 Italian institutions. We included all patients with enough follow-up to have at least one radiological evaluation during ICIs treatment. Patients with rapid clinical progression were included in the analysis. We analyzed response rate (RR), progression-free survival (PFS), and overall survival (OS). Response was evaluated using RECIST v1.1 criteria.
Result
75 patients were found, 64 included in the analysis. Mean age at diagnosis was 66.5 years (range 37-84), 65% were male. Histological type were: 76.5% adenocarcinoma, 14% squamous, 9.5% others, most with high PD-L1 expression (90.5% with ≥50% TPS). 58 patients (90.6%) were stage IV at ICIs start, with mean number of metastatic sites 1.8. Most patients were current/former smokers (87.5%); ECOG performance status (PS) at ICI start was: 0 in 34 pts (53.1%), 1 in 25 (39%), 2 in 5 (7.9%). 20 patients were receiving opioids at ICIs start (31.3%), with a mean daily dose equal to 59 mg of oral controlled-release morphine. With a median follow-up of 10.9 months, the median number of ICIs cycles was 7.5 (range 1-26). RR, mPFS and mOS in the whole series were 40.6%, 9.4 months and 17.1 months, respectively. Compared to the others, patients receiving opioids had numerically lower RR (30% vs 45.5%, p=0.24), a shorter PFS (median 12.7 vs 1.7 months, Hazard Ratio [HR] 4.16, 95%CI 2.15-8.05, p<0.001) and OS (median not reached vs 3.2 months, HR 4.68, 95%CI 2.09-10.52, p<0.001). At the multivariate analysis, opioid use continued to be significantly associated with worst PFS (HR 3.19, 95%CI 1.45-7.01, p=0.004) and OS (HR 4.16, 95%CI 1.61-10.76, p=0.003), even when accounting for PS, disease stage and number of metastatic sites.
Conclusion
Our results suggest a possible detrimental effect of opioids in aNSCLC patients treated with first line single-agent ICIs, even when correcting for other prognostic factors. However, due to the short follow-up, the small number of patients, and the lack of a control group, our results should be considered exploratory.
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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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P2.14-14 - Comparison of Molecular Testing Modalities for Detection of NRG1 Rearrangements in Invasive Mucinous Adenocarcinoma (ID 2179)
10:15 - 18:15 | Author(s): Massimo Di Maio
- Abstract
Background
The NRG1 (Neureguline-1) fusion gene has been recently described as a new molecular feature of non small cell lung cancer (NSCLC), strictly related to invasive mucinous adenocarcinoma (IMA) subtype. Despite of NRG1 fusion partners, all Nrg1 chimeric ligands were predicted to retain the EGF-like domain of the wild-type NRG1 III-β3 isoform that produces oncogenic signals through ErbB2-ErbB3 heterodimers and leads to phosphorylation of ErbB3. To date, the NRG1 fusions were quite exclusively identified by RNA sequencing and only in few cases confirmed by fluorescent in situ hybridization (FISH) analysis, mainly due to the cellular features of IMA subtypes that produce interference in fluorescent signals detection. An accurate detection of NRG1 rearrangement/fusions in clinical tumor samples is actually demanded. In this study we compared the performance of two molecular testing approaches to detect NRG1 breaks in paraffin embedded formalin fixed (FFPE) IMA lung tissues.
Method
A total of 19 lung FFPE IMAs were screened by immunohistochemistry (IHC) to evaluate the expression of phosphorylated-ErbB3 (pErbB3) receptor. Samples positive for pErbB3 staining were tested by using by break-apart FISH to detect putative NRG1 rearrangements and RNA-targeted next generation sequencing (NGS) to identify fusion variants.
Result
Eleven cases showed an increased expression of pErbB3 in cancer cells compared to the adjacent non-involving bronchial epithelium which demonstrated a basal level staining of the protein. pErbB3 positive cases were investigated by FISH and showed <15% of rearranged nuclei (range 17-47%, mean 29%). In addition to the canonical signal split pattern, the FISH NRG1 assay reveals that cells also showed rearrangement patterns in form of isolated 3’ signals, thus indicating a strength analogy with ALK and ROS1 fusions, where a 5’ gene deletion was frequently observed. CD74-NRG1 fusion variant was identified by NGS analysis in four cases, whereas in three cases a 3’/5’ NRG1 imbalance was detected. For both approaches, we identified assay characteristics that likely contributed to false-negative results.
Conclusion
Our investigations confirm the usefulness of IHC/FISH combined approach for NRG1 broken tumors identification, but also highlight the crucial role of NGS to identify NRG1 functional chimeric transcripts. Such combined molecular testing should enhance the selection of NRG1-positive patients to include in clinical trials with specific compounds designed to inhibit the RTK downstream signal.
