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Z. Xie
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-018 - Acquired Resistance to Crizotinib in Advanced NSCLC with De Novo MET Overexpression (ID 10014)
09:30 - 09:30 | Author(s): Z. Xie
- Abstract
Background:
MET exon14 skipping mutation has been regarded the driver mutation for MET activation, but with relatively low frequency of occurrence. MET overexpression can be a promising biomarker to predict the response to crizotinib. However, little is known about acquired resistance to treatments in tumors with de novo MET overexpression.
Method:
This prospective observational study included 33 NSCLC patients with MET IHC overexpression received crizotinib treatment From January 2013 to June 2017, 23 eligible patients evaluable for response . MET expression level were detected by immunohistochemistry (IHC) with antibody SP44, and ≥50% tumor cells with moderate to high intensity staining were defined as positive. Gene copy numbers were detected by FISH (Met probes from KREATECHTM.), and referring to Cappuzzo scoring system or MET/CEP7 ratio, ≥5 copies were positive or MET/CEP7 ratio ≥1.8 (low ≥1.8-≤2.2, Intermediate >2.2-<5 and High ≥5) was defined as MET amplification;. The status of EGFR, ALK, KRAS and ROS1 were also tested at baseline. Biopsy specimens obtained both at baseline and at the time of progression using targeted next-generation sequencing to assess for mechanisms of resistance.
Result:
Response were evaluable for 23 NSCLC patients with MET overexpression (4 female, 19 male). Fifteen of them achieved partial response (PR, 65.2%), 2 were stable disease (SD) and 6 were progressive disease (PD). All responders had high MET expression , and 12(52.2%) with FISH positive. The PFS and OS in the ITT population were 3.2 and 13.2 month respectively. Median PFS was 7.4m(95% CI,4.5-10.4) for MET IHC (100%+++) patients vs. MET IHC (50%++~100%+++) 1.9m (95% CI 0.9-2.9,P=0.053), For FISH positive patients, mPFS was 8.2 m(95% CI,5.2-11.1) m v.s. FISH negative 1.3m(95% CI,0.2-1.7,p=0.002). Two acquired resistance mechanisms were found after resistance, a 64 male patient with MET IHC 100%×3,FISH (+),crizotinib first line and the best response PR, rebiopsy after resistance showed the MET D1228N mutation by NGS, and the second patient was 50 years old male with MET IHC 100%×3,FISH (+),crizotinib first line and the best response was PR, EGFR amplification were found upon progression when rebiopsy after resistance. The patient acheived PR with subsequent treatment of cetuximab plus Taxel.
Conclusion:
Multiple mechanisms of acquired resistance to crizotinib were found in de novo MET overexpressed patients. A secondary mutation in the MET gene and EGFR amplification may be the two main mechanisms. MET overexpression could be as a biomarker for de novo MET positive NSCLC. FISH seems better in predicting efficacy for MET inhibitor.
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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.07-042 - PD-L1 and CD8 Expression in EGFR-Mutant or ALK-Rearranged Patients with Lung Cancer (ID 10407)
09:30 - 09:30 | Author(s): Z. Xie
- Abstract
Background:
Several studies indicate no response to check-point inhibitors on non-small-cell lung cancer with either EGFR-mutant or ALK-rearranged patients,of whom majority of international clinical trials involving PD-1/L1 inhibitors excluded. No solid evidences to interpret the underlying mechanism of poor clinical benefit to patients through PD-1/L1 inhibitors with driver genes mutation.
Method:
From 2010 to 2016, 482 patients and 263 patients with clinically operable lung cancer and advanced lung cancer respectively were collected at Guangdong Lung Cancer Institute (GLCI). All patients have detected for EGFR as well as ALK status. CD8 and PD-L1 expression was scored by immunohistochemistry with SP142 antibody. Five years survival rate was also analyzed.
Result:
Patients were assigned to EGFR/ALK positive group (344 cases) or negative group (401 cases). EGFR/ALK positive group contains 5.52% PD-L1+/CD8+; 11.92% PD-L1-/CD8+; 18.90% PD-L1+/CD8- and 63.66% PD-L1-/CD8-. EGFR&ALK negative group contains 13.97% PD-L1+/CD8+; 6.98% PD-L1-/CD8+; 30.42% PD-L1+/CD8- and 48.63% PD-L1-/CD8-. In EGFR/ALK positive group, PD-L1+/CD8+ is lower but PD-L1-/CD8- is higher than that of EGFR&ALK negative group (P<0.001). Significant statistical differences of 5 years survival rate were observed between four subgroups in EGFR/ALK positive group (PD-L1+/CD8+:41.9%, PD-L1-/CD8+: 91.0%, PD-L1+/CD8-: 75.4%, PD-L1-/CD8-: 69.7%; P=0.003). And there were no survival differences in EGFR&ALK negative group((PD-L1+/CD8+: 66.5%, PD-L1-/CD8+: 76.9%, PD-L1+/CD8-: 62.3%, PD-L1-/CD8-: 70.6%; P=0.341).
Conclusion:
Immunotherapy with PD-1/L1 inhibitors may not be suitable for EGFR-mutant or ALK-rearranged lung cancer patients with little co-expression of PD-L1 and CD8. However, these patients with such diver genes mutation reveal the best survival in PD-L1-/CD8+ subgroup and the worst survival in PD-L1+/CD8+ subgroup. Figure 1
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-054 - EGFR Mutation with Acquired C-MET Positive Reveals Potential Immunotherapeutic Vulnerabilities (ID 10436)
09:30 - 09:30 | Author(s): Z. Xie
- Abstract
Background:
There are few effective strategies for C-MET positive advance non-small-cell lung cancer(NSCLC) patients with epidermal growth factor receptor(EGFR) inhibitor resistance.The efficacy of PD-1 blockade immunotherapy and even the status of PD-L1 expression in such population is unclear.
Method:
Patients diagnosed as advanced NSCLC synchronously tested for EGFR status, expression of PD-L1 and C-MET at the Guangdong Lung Cancer Institute (GLCI) from 2015 to 2017 were collected.PD-L1 expression on tumor cells and immune cell was evaluated using a three-tiered grading system. C-MET positive was define as immunohistochemistry staining (2+/3+) in ≥ 50% of tumor cells. A chi-squared test was used to assess the relationships between C-MET positive and PD-L1 expression.
Result:
A total of 487 eligible cases were selected including 166 EGFR mutant and 321 wild type patients.In the general population(n=487),the difference of PD-L1 expression were observed between C-MET positive group and C-MET negative group (65.3% vs 31.7%, P=0.001),which was in accordance with the result from the Cancer Genome Atlas (TCGA) dataset (n=512,P<0.001).Furthermore,among the EGFR mutant patients (n=166), PD-L1 expression was showed in 58.1% of C-MET positive group and 28.5% of C-MET negative group,P value <0.001. Subsequently,T790M negative was identified in 55%(47/86) of EGFR TKI resistant patients (n=86).In this subgroup,a significant increase of PD-L1 expression was demonstrated in C-MET positive group compared to C-MET negative group(66.7% vs 34.6%,P=0.027).Finally, clinical efficacy of immunotherapy was further confirmed in 2 C-MET positive advanced lung adenocarcinoma patients with remarkable response to PD-1 blockade immunotherapy who had disease progression after C-MET inhibitors.Figure 1
Conclusion:
C-MET positive maybe associated with high PD-L1 expression in advanced NSCLC providing therapeutic insight into targeting the PD-1/PD-L1 pathway in EGFR inhibitor-resistant NSCLC with C-MET positive and T790M negative.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-063 - Concomitant EGFR Mutation and ALK Rearrangement in Non-Small-Cell Lung Cancer (ID 10058)
09:30 - 09:30 | Author(s): Z. Xie
- Abstract
Background:
The concomitance of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). We investigated the factors associated with the efficacy of targeted therapy and resistance mechanisms in EGFR/ALK co-altered NSCLCs.
Method:
EGFR mutation was identified with direct sequencing or Scorpion amplification refractory mutation system (ARMS). Relatively low EGFR-mutant abundance is considered as sequencing (-)/ARMS (+), while high abundance as sequencing (+). ALK-positive is assessed with any of the 3 methods: fluorescence in situ hybridization (FISH), rapid amplification of cDNA ends -coupled polymerase chain reaction and sequencing or Ventana immunohistochemistry (IHC). Next-generation sequencing was employed to analyze genetic profiles in patients with specimens before and after targeted therapy.
Result:
From December 2011 to December 2016, sixteen patients were identified with concomitant EGFR/ALK co-alterations, accounting for 0.6% (16/2632) in NSCLC patients, 1.8% (16/867) in EGFR-mutant and 8.6% (16/185) in ALK-positive patients. Five ALK-IHC (-)/FISH (+)/EGFR (+) patients with EGFR-TKIs experienced 3 PR, 1 SD and 1 waitiing for response evaluation, with median PFS of 11 months. Three with relatively low EGFR-mutant abundance achieved PR with crizotinib, while three with relatively high EGFR-mutant abundance obtained 2 PR and 1 SD with EGFR-TKIs. Spatial and inter-tumoral heterogeneity was observed in one EGFR/ALK co-altered patient. (Figure 1B) Two patients with T790M, one with Met pathway activation and two with loss of EGFR mutation were found after resistance to EGFR-TKIs. One with KRAS mutation was found pre- and post-EGFR-TKIs. ALK_F1174C mutation was observed in one patient after progression to crizotinib and ALK_G1202R mutation after resistance to ceritinib.Figure 1
Conclusion:
ALK protein expression, EGFR mutation abundance and tumor heterogeneity were associated with efficacy of targeted treatment for EGFR/ALK co-altered patients. Most mechanisms resistance to EGFR-TKIs and crizotinib were similar to those in typical EGFR mutation and ALK rearrangement respectively.
