Erlotinib Arm Research Articles

Thoracic radiation in combination with erlotinib-results from a phase 2 randomized trial.

Radiotherapy (RT) can be used to reduce symptoms and maintain open airways for patients with non-small cell lung cancer when systemic treatment is not sufficient. For some patients, tumor control is not achieved due to radioresistance. Concurrent inhibition of epidermal growth factor receptors has been proposed as a strategy to overcome radioresistance but may increase toxicity. We performed a randomized trial to assess the efficacy, tolerance, and quality of life of concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer. Patients were randomized 1:1 to RT alone (arm A) or in combination with erlotinib (arm B). A computed tomography (CT) scan at baseline and one at 4-12 weeks after inclusion was used to evaluate treatment response. Adverse events were registered during treatment and the subsequent 30 days. Health-related quality-of-life questionnaires were completed by the patients at baseline, weeks 2, 6, and 20. A total of 114 patients were included. Of the 74 patients with CT scans available for evaluation of treatment effect, there were no significant differences in tumor size reduction between the two groups: median 14.5% reduction in the control arm A and 17.0% in the erlotinib arm B (p = 0.68). Overall survival was not significantly different between the two treatment arms: 7.0 and 7.8 months in arm A and arm B, respectively (log-rank p = 0.32). There was no significant increase in adverse events in the experimental arm, other than what is expected from erlotinib treatment alone. Overall, patients reported similar quality of life in both treatment arms. Concurrent erlotinib and palliative thoracic RT for patients with advanced non-small cell lung cancer was well tolerated but did not improve the efficacy of the RT. ClinicalTrials.gov, identifier NCT02714530.

Impact of ramucirumab plus erlotinib on circulating cell-free DNA from patients with untreated metastatic non-small cell lung cancer with EGFR-activating mutations (RELAY phase 3 randomized study).

An exploratory, proof-of-concept, liquid biopsy addendum to examine biomarkers within cell-free DNA (cfDNA) in the RELAY phase 3, randomized, double-blind, placebo-controlled study was conducted. RELAY showed improved progression-free survival (PFS) with ramucirumab (RAM), a human immunoglobulin G1 vascular endothelial growth factor receptor 2 antagonist, plus erlotinib (ERL), a tyrosine kinase inhibitor, compared with placebo (PL) plus ERL. Treatment-naïve patients with endothelial growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer were randomized (1:1) to RAM + ERL or PL + ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations and EGFR-activating mutation allele counts were investigated by next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR), respectively. cfDNA concentration and fragment size were evaluated by real-time polymerase chain reaction and the BioAnalyzer. Patients with a valid baseline plasma sample were included (70 RAM + ERL, 61 PL + ERL). TP53 mutation was the most frequently co-occurring baseline gene alteration (43%). Post-study treatment discontinuation EGFR T790M mutation rates were 54.5% (6/11) and 41.2% (7/17) by ddPCR, and 22.2% (2/9) and 29.4% (5/17) by NGS, in the RAM + ERL and PL + ERL arms, respectively. EGFR-activating mutation allele count decreased at Cycle 4 in both treatment arms and was sustained at follow-up with RAM + ERL. PFS improved for patients with no detectable EGFR-activating mutation at Cycle 4 vs. those with detectable EGFR-activating mutation. Total cfDNA concentration increased from baseline at Cycle 4 and through to follow-up with RAM + ERL. cfDNA fragment size was similar between treatment arms at baseline [mean (standard deviation) base pairs: RAM + ERL, 173.4 (2.6); PL + ERL, 172.9 (3.2)] and was shorter at Cycle 4 with RAM + ERL vs. PL + ERL [169.5 (2.8) vs. 174.1 (3.3), respectively; P<0.0001]. Baseline vs. Cycle 4 paired analysis showed a decrease in cfDNA fragment size for 84% (48/57) and 23% (11/47) of patient samples in the RAM + ERL and PL + ERL arms, respectively. EGFR-activating mutation allele count was suppressed, total cfDNA concentration increased, and short fragment-sized cfDNA increased with RAM + ERL, suggesting the additional anti-tumor effect of RAM may contribute to the PFS benefit observed in RELAY with RAM + ERL vs. PL + ERL. ClinicalTrials.gov; identifier: NCT02411448.

Biological medicines for diffuse intrinsic pontine glioma (DIPG) eradication (BIOMEDE): Final results of an international randomized phase II platform trial comparing 3 targeted therapies in combination with radiotherapy from ITCC, SIOPE-Brain and ANZCHOG.

10003 Background: DIPG is the most aggressive brain cancer in children and adolescents with a median survival of 9 months. Surgery is not possible due to the invasive nature of the disease in a critical area of the brain; only radiotherapy has shown a transient palliative effect on disease progression and no adjuvant therapy has proven to increase disease control. Methods: We launched a large randomized biomarker-driven platform trial to compare three targeted therapies (erlotinib, everolimus and dasatinib) in combination with 54 Gy radiotherapy, in newly diagnosed patients with DIPG (NCT02233049). A central pathological review was performed prior to study entry to confirm the diagnosis of DIPG with H3K27me3 loss (with or without H3K27M mutation) and assess biomarkers. The randomization was designed so that a drug could not be allocated if the corresponding biomarker was absent in the tumor (EGFR overexpression for erlotinib, mTOR activation for everolimus, no specific biomarker for dasatinib). Tumors underwent whole genome sequencing and RNAseq to evaluate prognostic and theranostic biomarkers. Primary endpoint was overall survival. Results: Among the 279 DIPG patients screened for the randomized trial between October 2014 and September 2019, 233 were enrolled in 45 centers in 7 countries; among the 46 screen failures, the diagnosis of DIPG could not be confirmed in 23 patients. No biopsy- or treatment-related death was reported. Serious adverse events &gt; = 3 unrelated to disease progression were reported in 40% of patients, 34%, 36% and 46%, in the erlotinib, everolimus and dasatinib arms, respectively (p = 0.32). With a median follow-up of 5.3 years, median overall survival (OS) from the date of randomization was 9.0 (95% confidence interval, 7.4-14.4), 11.3 (10.3-13.4) and 9.4 (7.7-10.7) months for erlotinib, everolimus and dasatinib, respectively (p = 0.45). OS were not statistically different from those of a historical biopsy-proven cohort. The molecular profiling with copy number aberrations (CNA) had a strong impact on survival (log-rank test, p = 0.0001) as shown by the preliminary analysis of the first hundred patients identifying a group of tumors with very poor prognosis with a HR for death of 1.96 (1.07-3.64) characterized by TP53 mutations (p = 3.05e-11) associated with more CNA (p &lt; 0.0001). Conclusions: This trial demonstrated the feasibility and safety of a large randomized trial for DIPG based on biomarker information from a stereotactic biopsy at diagnosis in an international multicenter setting and generated new tumor biological insights to further develop innovative therapies. Clinical trial information: NCT02233049 .

Evaluation of Treatment Efficacy of Tyrosine Kinase Inhibitors in Rare Single EGFR Exon 21 L861Q Mutation: Single Center Experience.

OBJECTIVE:Epidermal growth factor receptor mutations are the second most common oncogenic driver event in non-small cell lung cancer. We aimed to compare the first generation erlotinib treatment with the second generation afatinib treatment in patients with non-small cell lung cancer with epidermal growth factor receptor exon 21 L861Q mutation.MATERIAL AND Methods:Progression-free survival and overall survival of 30 non-small cell lung cancer patients treated with erlotinib or afatinib due to single epidermal growth factor receptor L861Q positivity were compared retrospectively. The number of patients included in the first, second, and third treatment line was 15 (50.0%), 11 (36.7%), and 4 (13.3%), respectively.Results:There were 23 patients in the erlotinib arm and 7 patients in the afatinib arm. Median progression-free survival was 12.8 months in the erlotinib group and 9.3 months in the afatinib group. Median overall survival in erlotinib and afatinib groups was 77.9 months and 30.3 months, respectively. No statistically significant difference was found in the comparison of these survival times. Conclusion:Survival times of erlotinib and afatinib treatment are similar in patients with a single epidermal growth factor receptor L861Q mutation. In patients receiving tyrosine kinase inhibitors treatment, the female gender has a positive effect on progression-free survival, and being a non-smoker has a positive effect on overall survival. In patients with rare mutation exon 21 L861Q positivity, both first-generation and second-generation tyrosine kinase inhibitors should be considered.

PD-9 Three-arm phase II/III randomized controlled trial in patients with unresectable/metastatic gall bladder cancer with poor performance status: Erlotinib or capecitabine v/s best supportive care

Currently there is no standard of care for Eastern Cooperative Oncology Group (ECOG) poor performance status (PS) patients (PS-III) with unresectable/metastatic Gall Bladder Cancer (GBC). Being unfit for chemotherapy, these patients receive only best supportive care (BSC) resulting in a very dismal outcome. A report published from M.D. Anderson Cancer Centre stated median overall survival (OS) of only one month in patients with poor PS with GBC. This single centre, prospective randomized controlled phase II/III, open label trial was done at a tertiary health care centre in India. Patients (above 18 years) with histologically confirmed unresectable/ metastatic GBC with adequate organ function and ECOG PS-III were included. Patients with prior adjuvant chemotherapy/erlotinib/capecitabine in last 6 months, active malignancy other than GBC, lactating and pregnant women, and HIV-positive status were excluded. Random allocation (1:1:1) was done to one of the three arms - Erlotinib (150 mg OD) + BSC, Capecitabine + BSC or BSC alone using computer-generated sequence. The primary end point was median OS, defined as time from randomisation to death, in the intention-to-treat population. A sample size of 105 was estimated, assuming median OS in BSC, Erlotinib+BSC and Capecitabine+BSC as 2, 4 and 5 months respectively (taking two-sided alpha error as 0.05 and power as 80%). Between Dec 27, 2017 and January 18, 2021, 201 patients were screened, of which 105 were randomized to Erlotinib +BSC (n = 36), Capecitabine +BSC (n = 36) or BSC alone arm (n = 33). After a median follow up of 10 months (IQR 3.9- 11.5), there were 82 deaths in the whole cohort. The median OS in Erlotinib arm was significantly higher at 3.84 months (2.33- 4.67) compared to 1.77 months (1.18- 2.73) in BSC only arm, with hazard ratio (HR) of 0.50 (95% CI - 0.26 -0.95), p = 0.02. However, there was no statistically significant difference observed in survival between Capecitabine +BSC over BSC alone - median OS 2.46 months (1.67-3.58), HR - 0.70 (95% CI - 0.38- 1.2), p = 0.30. Compared to only 15.1% (5/33) in BSC arm, the disease control rate (complete response + partial response + stable disease) at 6-8 weeks was 58.3% (21/36) in Erlotinib arm (p = 0.004) and 47.2% (17/36) in Capecitabine arm (p = 0.04). Grade III/IV toxicities were reported in 12 patients (33.3%) in Erlotinib arm (skin rash and diarrhea being most common at 8% each) and in 5 patients (13.8%) in Capecitabine arm (anemia and fatigue most common at 6 % each). No treatment related deaths were reported in either group. Addition of Erlotinib to BSC significantly improves OS in patients with unresectable/metastatic GBC, otherwise unfit to receive chemotherapy, with acceptable toxicity profile.

Induction chemotherapy with or without erlotinib in patients with head and neck squamous cell carcinoma amenable for surgical resection.

Neoadjuvant chemotherapy prior to definitive surgery has been utilized widely for locally advanced oral squamous cell carcinoma (OSCC). We evaluated neoadjuvant erlotinib with platinum-docetaxel vs. placebo with platinum-docetaxel in stage III-IVB OSCC patients. Patients with newly diagnosed stage III, IVA, IVB (AJCC 7th) OSCC amenable to surgical resection were included. Patients were randomized to receive up to 3 cycles of chemotherapy with concurrent erlotinib or placebo, followed by surgery. The primary endpoint was major pathologic response (MPR) rate, secondary endpoints included safety, overall (OS) and progression-free survival (PFS). Fifty-two patients received at least one cycle of treatment and 47 were evaluable with surgical resection. MPR rate was not different between erlotinib (30%, 7/23) and placebo arms (41.7%, 10/24) (p=0.55). At median follow up of 26.5 months, there was no difference on OS or PFS between groups. Patients who received erlotinib with chemotherapy and achieved MPR (n=7) had no recurrence. The treatment-related adverse event rates were not different between the two groups (96% vs. 96%). However, rash, mostly low grade, was more common in the erlotinib arm (79% vs. 50%). Transcriptomic analysis in the pre-treatment samples indicated that genes in protein glycosylation and Wnt signaling pathways were associated with benefit in those treated with erlotinib plus chemotherapy. The addition of erlotinib to platinum-taxane chemotherapy was well-tolerated but did not induce higher rates of MPR or PFS or OS survival benefit. Patients who received chemotherapy with erlotinib and achieved major pathological responses had excellent clinical outcome.

EVALUATION OF THE ROLE OF GEMCITABINE AND ERLOTINIB IN STAGE IIIB AND STAGE IV NSCLC ADENOCARCINOMA OF LUNG AS A FIRST LINE CHEMOTHERAPY REGIMEN AND ASSESSING THE ACUTE TOXICITY, OVERALL SURVIVAL AND PROGRESSION FREE SURVIVAL RESPECTIVELY.

INTRODUCTION: 2 nd rd According to Globocan 2020 lung cancer is 2 most common malignancy in males and 3 most common in the females. st Previous studies have showed EGFR-tyrosine-kinase inhibitors erlotinib and getinib efcacy as 1 line treatment for patients with activating EGFR mutations. Also, Gemcitabine is drug of choice in inoperable and locally advanced metastatic NSCLC. With the purpose study was undertaken to evaluate the role of gemcitabine and erlotinib in stage IIIB and stage IV NSCLC adenocarcinoma of lung MATERIAL AND METHOD: 2 35 Patients with stage IIIB and IV fullling criteria were given Inj. Gemcitabine 1 gm/m D1 and D8 IV &amp; Tab erlotinib 150 mg PO daily repeated every 21 days, 6 cycles. Post 6 cycles of chemotherapy tab erlotinib 150 mg given till disease progression. Tumor response assessed by RECIST 1.1. Toxicity assessed by CTCAE version 5.0. RESULT: Adrenal metastasis was most common followed by lung, bone, malignant pleural effusion and liver metastasis. a median follows up in this study was 33 weeks. Toxicities noted were anemia, thrombocytopenia, febrile neutropenia, GI toxicities and rash. In post 3 cycles of chemotherapy, out of 35 patients,62.86 % were having partial response for primary and 34.29 % (n=12) for metastatic lesions. In post 6 cycles of chemotherapy there was a reduction in the partial response patients and a steep rise in stable disease patients. In Post 12 weeks of 6 cycles of chemotherapy more patients having a progressive disease, very little, 5.71 % having PR and 25.71 % were having a stable disease. DISCUSSION: The median PFS and median OS was 4.1 and 5.6 months respectively whereas Grade 3 toxicity was also seen in gemcitabine plus erlotinib arm. INTACT 1 trial-getinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial showed that getinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efcacy over gemcitabine and cisplatin alone. The median overall survival was 18.3 months and the median PFS was 7.6 months, in our study it come out to be 8.25 months and 4.5 months respectively. Also noted Grade 3 febrile neutropenia, anemia, thrombocytopenia, vomiting &amp; diarrhea same as our study. CONCLUSION: Standard treatment for patients with an activating EGFR mutation is rst-line single-agent EGFR-tyrosine kinase inhibitor and combination chemotherapy such as gemcitabine plus erlotinib is improving survival

The safety and efficacy of erlotinib and ramucirumab combination in EGFR-mutant non-small-cell lung cancer

ABSTRACT Introduction EGFR-tyrosine kinase inhibitors (TKIs) changed the natural history of EGFR-mutant advanced NSCLC patients, but acquired resistance is inevitable. New strategies are being tested to overcome or prevent the emergence of resistance mechanisms to first-line TKIs, among which combinations of TKIs with antiangiogenic agents. Areas covered We performed a literature search for preclinical and clinical data on the interplay and dual inhibition of EGFR/VEGF pathways, particularly in EGFR-mutant NSCLC. We then focused on RELAY, a placebo-controlled phase 3 trial evaluating ramucirumab combined to erlotinib in treatment-naïve advanced EGFR-mutant NSCLC patients. This article aims to summarize efficacy and safety of the ramucirumab-erlotinib combination in this setting. Expert opinion RELAY confirmed the clinical relevance of combining EGFR and VEGF(R)-targeting therapies, previously investigated in smaller phase 2–3 trials of erlotinib and bevacizumab. However, the meaningful PFS benefit observed in the ramucirumab + erlotinib arm is counterbalanced by the toxicity profile of ramucirumab and the need for bimonthly infusions. Pending OS results are, therefore, critical to assess the real benefit from this combination, especially as first-line osimertinib has improved survival in EGFR-mutant NSCLC patients and will probably remain the pivotal EGFR-TKI in this setting. However, its heterogeneous efficacy across subgroups paves the way for osimertinib-based combinations, which are being investigated in ongoing trials.

The efficacy of first-line tyrosine kinase inhibitors combined with co-medications in Asian patients with EGFR mutation non-small cell lung cancer

The real-world efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations remains unclear. We conducted a retrospective cohort study using data from the claims database of Taipei Veterans General Hospital to perform direct comparisons of these three EGFR-TKIs (gefitinib, erlotinib, and afatinib) combined with co-medications (metformin, statins, antacids, and steroids). Stage IIIB and IV NSCLC patients with EGFR mutations receiving EGFR-TKIs as first-line treatment for > 3 months between 2011 and 2016 were enrolled. The primary endpoint was time to treatment failure (TTF). Patients who had received co-medications (≥ 28 defined daily doses) in the first 3 months of EGFR-TKI therapy were assigned to co-medications groups. A total of 853 patients treated with gefitinib (n = 534), erlotinib (n = 220), and afatinib (n = 99) were enrolled. The median duration of TTF was 11.5 months in the gefitinib arm, 11.7 months in the erlotinib arm, and 16.1 months in the afatinib arm (log-rank test, P < 0.001). After adjustments, afatinib showed lower risk of treatment failure compared with gefitinib (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.41–0.71) and erlotinib (HR 0.62, 95% CI 0.46–0.83). The risk of treatment failure in patients treated with EGFR-TKIs who received concomitant systemic glucocorticoid therapy was higher than in those treated with EGFR-TKI monotherapy (HR 1.47, 95% CI 1.08–2.01). Afatinib or erlotinib use was associated with a lower risk of treatment failure in patients with advanced NSCLC harboring EGFR mutations compared to gefitinib use. Concurrent use of systemic glucocorticoids was linked to higher risk of treatment failure.

Randomized phase 3 open label study of quality of life of patients on Pemetrexed versus Erlotinib as maintenance therapy for advanced non squamous non EGFR mutated non small cell lung cancer.

Background: We planned to compare pemetrexed maintenance with erlotinib maintenance in non squamous non Epidermal Growth Factor Receptor (EGFR) mutated non small cell lung cancer (NSCLC). The null hypothesis for this study was that there would be no difference in quality of life (QOL) between pemetrexed and erlotinib maintenance. Results: The QL2 scores at 3 months were 63.35 (SD 24.99) in pemetrexed arm and 63.01(SD 23.04) in erlotinib arm (p-0.793). Except in 1 domain, the scores were statistically similar between the 2 arms. In the domain of diarrhea, the score was higher as expected in the erlotinib arm (p-0.048). The median progression free survival was 4.5 months (95%CI 4.1–4.9 months) in pemetrexed arm versus 4.5 months (95%CI 3.8–5.2 months) in erlotinib arm (p-0.94). The median overall survival was 16.6 months (15.2–17.9 months) in pemetrexed arm versus 18.3 months (95% CI 13.75–22.91 months) in erlotinib arm (p-0.49). Methods: The study was an open label, single centre, parallel, phase 3 randomized study with 1:1 randomization between maintenance pemetrexed arm and erlotinib arm. Adult patients (age > or = 18 years), with non squamous EGFR mutation, treated with first line palliative therapy, with non progressive disease post 4–6 cycles of pemetrexed-carboplatin were randomized. Primary outcome was change in the score of QOL (Global health status {QL2}) at 3 months. We estimated that with 200 patients, the study had 80% power to detect a significant difference between the two groups in the change in the global health status score at 3 months with an alpha error of 5%, with an effect size of 0.3 SD. Conclusions: Maintenance pemetrexed post pemetrexed-platinum chemotherapy fails to improve QOL or time to event outcomes over maintenance erlotinib in EGFR mutation negative NSCLC.

Effect of Erlotinib Plus Bevacizumab vs Erlotinib Alone on Progression-Free Survival in Patients With Advanced EGFR-Mutant Non–Small Cell Lung Cancer

Erlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months. To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone. This phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018. Patients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. The primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months). Among 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR, 0.81; 95% CI, 0.50-1.31; P = .39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P = .81), and OS (HR, 1.41; 95% CI, 0.71-2.81; P = .33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients. Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC. ClinicalTrials.gov identifier: NCT01532089.

A phase II randomized control trial of erlotinib in combination with celecoxib in patients with operable oral squamous cell carcinoma (OSCC): Erlo-Xib Study.

6054 Background: When combined with COX-2 inhibitors, the EGFR tyrosine kinase inhibitor Erlotinib has shown a better antitumor response in preclinical studies. Since high volume hospitals in many countries usually have a longer waiting period for surgery, neoadjuvant targeted therapy may be helpful in reducing disease progression and downstaging oral squamous cell cancers. Methods: Sixty-four treatment-naïve operable oral cancer patients were randomized into a four-arm window of opportunity study consisting of treatment with erlotinib 150mg daily, celecoxib 200mg twice daily, the combination of both or observation alone (NCT02748707). Since the regular wait period for surgery at our hospital was four to five weeks, we planned a 21-day drug treatment versus observation followed by definitive surgery in the fourth week. MRI scans and biopsies were done before and after drug treatment. Post-operative adjuvant treatments were given as per the standard guidelines used for regular patients. Results: There were 10 females and 54 males with a mean and median age of 44 and 45 years respectively. Taking a 20% reduction in the maximum tumor dimension after drug treatment (assessed clinically and radiologically) as partial response, the combination arm had a 60% partial response and a 25% stable disease. Whereas, 60% in the control arm had disease progression. The ratio of the longest tumor dimension at day 21 versus day 0 (Clinical &amp; MRI assessment) also showed a significant difference between the observation vs erlotinib arms (p &lt; 0.001) using Mann-Whitney Test. Grade II/III rashes was the commonly observed toxicity predominantly in the combination arm. Though not powered for survival analysis, a significant difference (p = 0.048) was observed for two-year overall survival for celecoxib + control (60%) versus erlotinib + combination groups (86%) using Kaplan Meier estimator. Biomarker analysis (transcriptome sequencing and IHC) is being done on pre and post-treatment tumor specimens and the final results will be presented. Conclusion: Preoperative targeted therapy with erlotinib and celecoxib combination can arrest disease progression and downstage tumors with possible impact on survival. The identified biomarkers can further refine a future cohort for effective neoadjuvant targeted therapy in oral cancers. Clinical trial information: CTRI/2012/07/002828.

Induction chemotherapy with and without erlotinib in patients with oral cavity squamous cell carcinomas (OCSCCs) amenable for surgical resection.

6067 Background: We have previously demonstrated activity of erlotinib in head and neck SCCs as monotherapy prior to surgical resection, or in combination with chemotherapy for recurrent/metastatic disease (William et al. ASCO 2011, 2017). The aim of this study was to evaluate the efficacy of induction chemotherapy with a platinum-taxane regimen and explore the potential benefit of erlotinib as part of induction therapy in patients with resectable OCSCCs. Methods: This was a randomized, placebo-controlled, phase II trial of induction chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 6 with docetaxel 75 mg/m2 every 3 weeks for 3 cycles) with erlotinib (150mg oral daily) or placebo in patients with OCSCCs stage III-IVB amenable for surgical resection. The primary endpoint was major pathological response (MPR, defined as &lt; 10% viable tumor cells in the surgical specimen). Secondary endpoints included safety and long-term efficacy outcomes. Results: From April 1, 2014, to June 7, 2017, 52 patients were enrolled, of whom 47 underwent planned surgery. MPR was achieved in 7/23 (30%) in the erlotinib group and 10/24 (41%) in the placebo group. With a median follow up of 26.5 months, the 2-year long-term progression-fee survival (PFS) were estimated at 75% (95% CI: 59.5-94.5) in the erlotinib arm, and 58.6% (95% CI: 40.9-84.1) in the placebo arm, and 2-year overall survival at 73.5% (95% CI: 57.2-94.5) for the erlotinib group and 73.1% (95% CI: 55.9-95.6) for the placebo group. In patients who achieved MPR (n = 17), the 2-year PFS was 77.4% (95% CI: 57.3-100), compared to 64.5% (95% CI: 49.0-84.8) in patients who did not achieve MPR (n = 29, p = .16). All 7 patients in the erlotinib group who achieved MPR remained disease-free. The majority of patients (87%) completed all 3 cycles of induction chemotherapy. The common side effects were expected and distributed similarly between erlotinib and placebo groups. As expected, rash, diarrhea and dehydration were more common in the erlotinib group. Conclusions: Platinum and docetaxel-based induction chemotherapy induced major pathological response in 17/47 (36%) of resectable OCSSC patients. Two-year overall survival was 73%. Responders had improved long-term outcome. Addition of erlotinib did not improve the rate of MPR, but might have contributed to improved PFS. Clinical trial information: NCT01927744.

MA08.01 Phase 3 Trial of Whole Brain Radiotherapy with Concurrent Erlotinib Versus WBRT Alone for NSCLC with Brain Metastases (ENTER)

Brain metastasis (BM) is a leading cause of death for non-small cell lung cancer (NSCLC). Whole Brain Radiotherapy (WBRT) is a standard-of-care treatment for NSCLC patients with multiple brain metastases. Elevated EGFR expression and activity are important causes of tumor resistance to radiotherapy. This phase 3 trial sought to determine if concurrent erlotinib with WBRT will benefit patients with multiple BM compared with WBRT alone. In this open-label, randomised, multicenter phase 3 study in China (NCT01887795), we enrolled NSCLC patients with at least two metastatic brain lesions who were naive to brain radiation and free from any EGFR-TKI for at least 4 weeks. Participants were randomly assigned (1:1) to receive either WBRT (2.0 Gy per day, 5 days per week, to 40 Gy) or WBRT plus concurrent oral erlotinib 150 mg daily (Erlotinib was given for 6 days then concurrently with WBRT). Subsequent treatments were maintenance therapy of erlotinib for EGFR-positive patients or standard chemotherapy for EGFR-negative patients until unacceptable adverse events or disease progression. The primary endpoint was intracranial progression-free survival (iPFS), defined as time from randomisation to either intracranial disease progression or death for any cause. Between August 7, 2013 and November 25, 2016, in total 222 patients from 11 centers across China were randomized to treatments: 115 with WBRT alone and 107 with WBRT and concurrent erlotinib. Median follow-up was 11.2 months (IQR 4.6-18.2). Median iPFS was 11.2 months (95% CI: 7.2-13.7) with WBRT and concurrent erlotinib versus 9.2 months (95% CI: 6.7-10.9) with WBRT alone (HR 0.926; 95% CI: 0.695-1.234; P=0.601). In the subgroup of 109 patients who were positive for the EGFR mutation, iPFS was not significantly longer among those who received WBRT with concurrent erlotinib than WBRT with sequential erlotinib (14.6 [95% CI 11.8-17.7] vs 12.8 [7.9-14.9] months; HR 0.743; 95% CI: 0.489-1.129; P=0.164). Median PFS of concurrent erlotinib arm was 5.3 months versus 4.0 of WBRT alone (HR 0.969; 95% CI: 0.735-1.277; P=0.825) and median overall survival (OS) was 12.9 versus 10.0 months (HR 0.913; 95% CI: 0.680-1.226; P=0.545). This multi-institutional study demonstrated WBRT with concurrent erlotinib improved neither iPFS significantly than WBRT alone in the intention-to-treat population and the EGFR-positive subgroup, nor improved PFS or OS in intention-to-treat population, indicating that erlotinib played limited role when concurrently used with WBRT and for EGFR-positive NSCLC patients, WBRT with concurrent erlotinib was not significantly superior to WBRT with sequential erlotinib.

P13 Impact of ErbB Mutations on Clinical Outcomes in Afatinib- or Erlotinib-Treated Patients with SCC of the Lung

In LUX-Lung 8 (LL8), second-line afatinib (an irreversible ErbB family blocker) significantly improved OS (median 7.9 versus 6.8 months; HR [95% CI]: 0.81 [0.69‒0.95]; p=0.0077), and PFS (2.6 versus 1.9 months; 0.81 [0.69‒0.96]; p=0.0103) versus erlotinib in lung SCC (N=795). Comprehensive genetic analysis in LL8 patients assessed whether afatinib efficacy varied according to genetic aberrations in cancer-related genes, including ErbB family mutations. Tumor genetic analysis (TGA) was performed using Foundation Medicine FoundationOne™ next-generation sequencing (NGS). The cohort was enriched for patients with PFS >2 months, reflecting a range of responsiveness to EGFR-TKIs. EGFR expression was assessed by immunohistochemistry (IHC) in a largely separate cohort. Cox regression analysis correlated PFS/OS with genetic mutations (individual/grouped) and EGFR expression. Of 440 patients selected for TGA (PFS >2 months: n=320; ≤2 months: n=120), samples from 245 were eligible (afatinib: n=132; erlotinib: n=113). In the selected TGA population, PFS/OS outcomes were improved in the afatinib versus erlotinib arm. Baseline characteristics were similar in TGA and IHC cohorts and LL8 overall. In the TGA subset, 53 patients (21.6%) had ≥1 ErbB family mutation (EGFR: 6.5%; HER2: 4.9%; HER3: 6.1%; HER4: 5.7%). Beyond the benefit seen for afatinib in the overall population, in afatinib-treated patients PFS/OS were longer when ErbB mutations were present (PFS: 4.9 versus 3.0 months; OS: 10.6 versus 8.1 months). Conversely, survival outcomes in erlotinib-treated patients were similar with/without ErbB mutations. Presence of HER2 mutations predicted favorable PFS/OS with afatinib versus erlotinib. The Table shows outcomes in patients with/without ErbB family mutations, and by EGFR expression levels (afatinib: n=157; erlotinib: n=188). These data are provocative and suggest that NGS may enable identification of lung SCC patients who would derive additional clinical benefit from afatinib. Differential outcomes with respect to ErbB mutations for afatinib and erlotinib are hypothesized to reflect afatinib’s broader mechanism of action. Clinical trial identification: NCT01523587

432P - QTWiST analysis to compare the benefit of maintenance Erlotinib versus pemetrexed patients with EGFR non mutated NSCLC

Background: In an open label, Phase 3 randomised study, Pemetrexed maintenance after induction with 4-6 cycles of pemetrexed -Platinum therapy failed to prove its superiority over Erlotinib in patients with EGFR non mutated NSCLC. In this analysis we have assessed the benefit of erlotinib over Pemetrexed using quality adjusted time without symptom or toxicity analysis method. Methods: The overall survival in each arm was partitioned into 3 health states. TOX state (Time spent in grade 3 or above toxicity after randomization and before progression), TWiST state (Time spent after randomization before progression without grade 3 or above toxicity) and REL state (Time spent after progression). The mean QTWiST was calculated for each arm using utility coefficients of 0.65 for TOX, 0.71 for TWiST and 0.67 for REL states respectively. The difference in QTWiST and the 95% CI of difference were calculated using a nonparametric bootstrap. A p value of 0.05 was considered as significant. Results: The mean TOX duration was 2.216 days in Erlotinib arm versus 1.359 days in pemetrexed arm, p = 0.572. The mean TWiST duration was 215.85days in Erlotinib arm versus 217.605 days in pemetrexed arm, p = 0.945. The mean REL state duration was 198.620 days in Erlotinib arm versus 196.254 days in maintenance pemetrexed arm, p = 0.932. There was no statistically significant difference between the two arms in mean TOX duration, mean TWiST duration and mean REL state duration. The mean QTWiST was 287.770 days in Erlotinib arm versus 286.873 days in Pemetrexed arm. The difference was of -0.897 days (95% CI -22.475 - 20.681, p value 0.935). Conclusions: The mean QTWiST of Erlotinib arm was similar to maintenance Pemetrexed arm. Our results failed to prove the benefit of Erlotinib over Pemetrexed maintenance post induction with 4-6 cycles of pemetrexed -Platinum therapy in terms of quality adjusted time without toxicity. Legal entity responsible for the study: Department Of Medical Oncology Tata Memorial Hospital, Mumbai Funding: None Disclosure: All authors have declared no conflicts of interest.

EGFR mutational status in determining choice of TKIs or standard chemotherapy for patients with advanced non-small cell lung cancer

Background: Tyrosine Kinase Inhibitors are important therapeutic resources for Non-Small Cell Lung Cancer (NSCLC) patients (pts) expressing EGFR-activating mutations (EGFR-m). However, pts without EGFR-addicted tumors do not display the same benefit. Nevertheless, Erlotinib can currently be prescribed to NSCLC pts after failure of a first-line treatment regardless of their EGFR status. Material (patients) and methods: We retrospectively analysed 143 pts diagnosed with advanced NSCLC between 2005 and 2016 and followed in two different Oncology Divisions. Sixty-nine pts presented EGFR-m while 74 displayed wild-type (WT) EGFR. We initially compared the Progression Free (PFS) and Overall Survival (OS) of the EGFR-m population according to it’s therapeutic sequence i.e. TKIs as first line followed by chemotherapy at progression versus first line chemotherapy followed by anti-EGFR TKIs in second line. We then analysed the PFS and OS of EGFR-wt pts treated with conventional chemotherapy or Erlotinib after failing a standard platinum doublet as first line. Results: In EGFR-m pts median PFS was 11 months in the TKI group and 6 months in those receiving chemotherapy (HR 0.59 CI 95% 0.34-1.04; p = 0.01). However, OS was similar in the two arms: 21 months among pts receiving TKIs in first line and 26 months in pts receiving chemotherapy as first line (HR 1.24, CI 95% 0.69-2.22; p = 0.31). In the EGFR-wt group, median PFS after second line was 5 months in the standard chemotherapy arm and 3 months in the Erlotinib arm (HR 0.76, CI 95% 0.45-1.30; p = 0.01). Differences in the two groups were also significant for OS (26 months among pts receiving chemotherapy and 19 months for those receiving Erlotinib in second line HR 0.67, CI 95% 0.40-1.14; p 0.05). Conclusions: Our study confirms, in an unselected Sicilian population, that EGFR mutations are a strong predictor of TKI benefit. Hence, EGFR-m pts should receive a TKI as first-line treatment as this was associated with improved PFS, although we observed no differences in OS. Moreover, this study suggests the importance of second line standard chemotherapy in subjects with wild-type EGFR since, in this population, TKIs generate inferior responses in terms of both PFS and OS.

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

Retrospective analysis of survival in patients with leptomeningeal carcinomatosis from lung adenocarcinoma treated with erlotinib and gefitinib.

Leptomeningeal carcinomatosis is a relatively rare metastatic form of non-small cell lung cancer, which can impact prognosis. There is an increasing need for selecting suitable epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors among those currently included in standard care for EGFR mutation-positive patients. We compared the efficacy of gefitinib and erlotinib in survival of patients with leptomeningeal carcinomatosis. The medical records of 269 patients who received tyrosine kinase inhibitors at a single center were retrospectively reviewed. Overall, 22 patients (8.2%) were treated with tyrosine kinase inhibitors for leptomeningeal carcinomatosis from non-small cell lung cancer with EGFR mutation between 2006 and 2016. Time to death from leptomeningeal carcinomatosis diagnosis was compared between the gefitinib and erlotinib groups. Gefitinib and erlotinib were administrated to 5 and 17 patients, respectively. Median progression-free survival was longer in the erlotinib group than in the gefitinib group (6.60 vs 2.12 months, P = 0.07). Overall survival was more than twice as long in the erlotinib arm compared with that in the gefitinib arm (7.20 vs 2.99 months, P = 0.32). Response in patients with exon 19 deletion was better than in those with exon 21 mutation (overall survival, 7.20 and 5.62 months, respectively, P = 0.12). Erlotinib seemed more effective than gefitinib in prolonging survival in leptomeningeal carcinomatosis from EGFR mutation-positive non-small cell lung cancer and may be particularly beneficial in patients with EGFR exon 19 mutations, warranting further studies.

ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC

ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC