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Manuel Cobo Dols
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MA15 - Colliding Approaches - EGFR and Immunotherapy (ID 916)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 13:30 - 15:00, Room 107
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MA15.03 - PD-L1 Expression in Untreated EGFRm Advanced NSCLC and Response to Osimertinib and SoC EGFR-TKIs in the FLAURA Trial (ID 12989)
13:40 - 13:45 | Author(s): Manuel Cobo Dols
- Abstract
- Presentation
Background
In the Phase III FLAURA trial (NCT02296125), osimertinib significantly improved PFS relative to SoC EGFR-TKIs (gefitinib/erlotinib) in patients with untreated Ex19del/L858R positive (EGFRm) NSCLC. EGFRm NSCLC tumors can exhibit high PD-L1 expression, an important biomarker for immunotherapy treatment decisions. The frequency and clinical relevance of exhibiting both biomarkers prior to treatment are unclear. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following EGFR-TKI treatment.
a9ded1e5ce5d75814730bb4caaf49419 Method
Tissue samples from 994 patients with advanced NSCLC were screened for EGFR Ex19del/L858R mutations for enrolment in FLAURA; 556 were randomized to treatment. 197 tissue-blocks from the screened population (including EGFR mutation-positive and -negative samples) were tested for PD-L1 using the SP263 (Ventana) immunohistochemical assay; positive tumour cell (TC) staining PD-L1 TC≥25% and TC≥1% thresholds were applied. PFS was investigator-assessed, per RECIST 1.1, according to PD-L1-expressers (TC≥1%) or -negatives (TC<1%) in randomized patients.
4c3880bb027f159e801041b1021e88e8 Result
193/197 blocks had sufficient tumor tissue for staining. 65/193 patients were EGFR mutation-negative. 128/193 patients were EGFR mutation-positive: 106/128 were randomized to treatment (osimertinib: 54; SoC: 52). The table presents PD-L1 expression according to EGFR mutation status. For PD-L1-expressers (TC≥1%), median PFS was 18.4 months for osimertinib and 6.9 months for SoC (HR 0.30 [95% CI 0.15, 0.60]). For PD-L1-negative patients (TC<1%), median PFS was 18.9 months for osimertinib and 10.9 months for SoC (HR 0.37 [95% CI 0.17, 0.74]).
8eea62084ca7e541d918e823422bd82e ConclusionPD-L1 TC≥1%, n (%)
PD-L1 TC≥25%, n (%)
EGFR mutation-negative (n=65)
Screened population (n=65)
44 (68)
23 (35)
EGFR mutation-positive (n=128)
Screened population (n=128)
65 (51)
10 (8)
Randomized to treatment (n=106)
52 (49)
8 (8)
Randomized to osimertinib (n=54)
28 (52)
3 (6)
Randomized to SoC EGFR-TKI (n=52)
24 (46)
5 (10)
There was PFS benefit with osimertinib versus SoC regardless of whether tumors were PD-L1-expressers (TC≥1%) or -negatives (TC<1%). Using the TC≥25% threshold, PD-L1 prevalence was lower in EGFR mutation-positive than mutation-negative samples; there were insufficient patients with TC≥25% tumors for PFS assessment.
These results support the efficacy of EGFR-TKIs, including osimertinib, as first-line treatment of EGFRm advanced NSCLC, irrespective of PD-L1 expression.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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OA01 - Improving Outcomes in Locoregional NSCLC I (ID 892)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 107
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OA01.05 - Phase II Study of Neo-Adjuvant Chemo/Immunotherapy for Resectable Stages IIIA Non-Small Cell Lung Cancer- Nadim Study-SLCG (ID 12907)
11:15 - 11:25 | Author(s): Manuel Cobo Dols
- Abstract
- Presentation
Background
The combination of chemotherapy and immunotherapy (CT-IO) has a high response rate and longer survival in unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). There are no data about this combination in the neoadjuvant setting.
a9ded1e5ce5d75814730bb4caaf49419 Method
A Phase II, single-arm, open-label multicenter study of local-advanced resectable stage IIIA N2-NSCLC adult patients with CT plus IO (nivolumab (NV)) followed by adjuvant treatment for 1 year. Neoadjuvant treatment: Three cycles of NV 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W. After completing neoadjuvant therapy, tumor assessment is performed in patients prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. Adjuvant treatment: NV 240mg IV Q2W for 4 months and NV 480mg IV Q4W for 8 months (total one year) after surgical resection. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present preliminary data on patients that completed 3 cycles and underwent surgical resection.
4c3880bb027f159e801041b1021e88e8 Result
At the time of submission, 46 pts had been included and 20 underwent surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts was withdrawn from the study preoperatively due to progression or toxicity.
Twenty surgeries had been performed and all tumors were deemed resectable. The overall clinical response rate was 5% complete (CR) and 65% PR. The pathological response evaluated after surgery: 13 cases (65.0%) achieved CR (CPR) (95% CI 40.8-84.6%), and 3 (15.0%) had a major pathologic response (MPR), defined as <10% viable tumor cells in the resection specimen. Considering both CPR and MPR, the overall response rate was 80.0% (95% CI 56.3-94.3%) and 60% of complete responses were unsuspected
8eea62084ca7e541d918e823422bd82e Conclusion
This is the first multicentric study testing CT-IO in the neoadjuvant setting with promising antitumor activity in locally advanced, potentially resectable NSCLC yields an unprecedented complete pathologic response rate. The data will be updated at the time of the congress. EudraCT Number: 2016-003732-20
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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P1.13-01 - Anti-EGF Antibodies Increase the Effect of ALK and MEK Inhibitors in ALK and KRAS NSCLC and CRC Cell Lines (ID 13160)
16:45 - 18:00 | Author(s): Manuel Cobo Dols
- Abstract
Background
Immunization against Epidermal Growth Factor (EGF) has demonstrated efficacy in a phase III trial including unselected NSCLC patients, and we have recently shown that antibodies generated by vaccination (anti-EGF VacAbs) potentiate the effects of TKIs in EGFR-mut cells growing in vitro. In this study, we aimed to determine if anti-EGF VacAbs show antitumor activity in KRAS-mutant (mut) and Anaplastic Lymphoma Kinase (ALK) translocated non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) cells, alone or in combination.
a9ded1e5ce5d75814730bb4caaf49419 Method
Anti-EGF VacAbs were generated in rabbits. Cell lines were treated with anti-EGF VacAbs alone and in combination with ALK TKIs, trametinib and standard chemotherapeutic agents in ALK translocated (H3122, E13;A20 (v1) and H2228, E6;A20 (v3)) and lung (A549 and H23) and colon (DLD1 and LS174T) KRAS-mut cell lines. Cell viability was analyzed by MTT, changes of total and phosphorylated proteins by Western blot and emergence of resistance by direct microscopic examination in low density cultures.
4c3880bb027f159e801041b1021e88e8 Result
Anti-EGF VacAbs suppressed EGF-induced cell proliferation and inhibited EGFR phosphorylation signaling in all cell lines tested. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of alectinib and crizotinib in H2228 cells and trametinib in A549, H23 and DLD1 cells. In these cell lines, the antibodies decreased Erk ½ and Akt phosphorylation. Finally, the addition of the anti-EGF VacAbs to the culture medium significantly delayed the emergence of resistant clones to alectinib and crizotinib in H2228 cells. In previous experiments, H2228 cells had shown a stronger dependency on the EGF/EGFR pathway than H3122. Results for the combination with standard chemotherapy in KRAS-mut cell lines will be presented at the meeting.
8eea62084ca7e541d918e823422bd82e Conclusion
Anti-EGF VacAbs decreased cell proliferation and inhibited EGFR activation in lung and colon ALK translocated and KRAS-mut cell lines. In addition, they potentiated the effects of trametinib in KRAS-mut cells and TKIs in ALK translocated cells (v3), where they also prevented the emergence of resistance to alectinib and crizotinib. Two clinical trials are currently testing anti-EGF vaccination in advanced NSCLC; the Epical Phase I/II trial, in combination with EGFR TKIs in EGFR-mut patients; and the BV-NSCLC-002 Phase III trial, in combination with chemotherapy in EGFR-wt.
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P1.13-36 - Randomized Phase 2 Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer (ID 13960)
16:45 - 18:00 | Author(s): Manuel Cobo Dols
- Abstract
Background
Seribantumab (MM-121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3), to block heregulin (HRG/NRG)-mediated ErbB3 signaling and induce receptor downregulation. This open-label, randomized Phase 1/2 study evaluated safety and efficacy of seribantumab in combination with erlotinib in advanced NSCLC. Here, we report the activity of seribantumab in combination with erlotinib, versus erlotinib alone, in patients with EGFR wild-type tumors and describe the potential predictive power of HRG.
a9ded1e5ce5d75814730bb4caaf49419 Method
Patients with EGFR wild-type NSCLC were assigned randomly to receive seribantumab plus erlotinib or erlotinib alone. Patients underwent pre-treatment core needle biopsy, and archived tumor samples were collected to support pre-specified biomarker analyses.
4c3880bb027f159e801041b1021e88e8 Result
One hundred twenty-nine patients received seribantumab/erlotinib (n=85) or erlotinib alone (n=44). Median estimated PFS in the unselected ITT population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (HR=0.822; 95% CI, 0.37 to 1.828; P=0.63). In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab/erlotinib combination (HR=0.35; 95% CI, 0.16 to 0.76; P=0.008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97 to 4.76; P = 0.059).
8eea62084ca7e541d918e823422bd82e Conclusion
The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, pre-defined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial is validating this finding in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216).
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.04 - Immunooncology (Not CME Accredited Session) (ID 953)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.04-24 - Nivolumab in the "Real World": Are the Results of Clinical Trials Reproducible? (ID 12404)
16:45 - 18:00 | Author(s): Manuel Cobo Dols
- Abstract
Background
It have passed more than two years since the approval of nivolumab in the second or third lines of treatment of non-small cell lung cancer (NSCLC) in advanced or recurrent stages, so that we know the results in patients in our area.
a9ded1e5ce5d75814730bb4caaf49419 Method
The main objective of this study is to analyze the results in a "real" population of different hospitals in Spain since we will be able to compare our results with the once published previously.
We have reviewed 129 patients with NSCLC, advanced or recurrent stages, treated with nivolCutumab either in second and subsequent lines of treatment, after progression to a platinum-based scheme from its expanded use until April 2018, in five hospitals in Spain.
The information was collected retrospectively of clinical, analytical, pathological and treatment characteristics of the patients. Statistical analysis was performed using the SPSS software vs 21.0, considering the statistical significance if p <0.05
4c3880bb027f159e801041b1021e88e8 Result
With a median follow-up of 6 months (0-31), the overall survival (OS) was 9 months (5.86-12.14).
8eea62084ca7e541d918e823422bd82e Conclusion
Patients with ECOG 0-1 presented a median OS of 11 months compared to 3 months of median OS in patients with ECOG 2 (p: 0.001)
If the response to previous treatment was complete response, partial response or stabilization of the disease, they will have a median OS of 12 months compared to 6 months if the best response was progression (p: 0.002).
There is also a statistically significant difference in terms of overall survival in relation to the existence of toxicity for immunotherapy or not (median of 13 versus 6 months p: 0.004).
The overall survival of patients who had progressed beyond 6 months after the start of treatment with prior chemotherapy was significantly greater than patients who had progressed in the first 6 months after the start of chemotherapy (median of 4 months versus median of 13 months, p: 0.001)
Immunotherapy has come to stay taking part of the usual clinical practice of patients with lung cancer. The results obtained in our population are comparable to those previously published, with an important group of patients that responded to immunotherapy or stabilized even for a long time. However, we highlight that also there is a percentage of patients, who progress early. We see fundamental to find or recognize, not just the ideal biomarker that helps to predict response, but those clinical characteristics that can make us presage a poor result.
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