Epidermal growth factor receptor intron 1 (CA)n dinucleotide repeat polymorphism and mutations associated with the responsiveness of molecular targeted therapy in lung cancer

e14595 Background: To explore EGFR gene intron 1 (CA)n repeat polymorphism and mutations associated with the responsiveness of molecular targeted therapy in lung cancer. Methods: Both observed groups consisted of 116 somatic specimens of lung cancer and controls consisted of 20 peripheral blood samples were analyzed by direct DNA sequencing of EGFR mutations at exons 18,19,21. Also (CA)n repeat polymorphisms in intron 1 of EGFR from 48 specimens were analyzed. 45 lung cancer patients were followed up. Results: EGFR mutations were found in 24 of 116 somatic specimens (20.69%). Response rate and disease control rate to EGFR TKIs was significantly higher in the patients with EGFR mutations (62.5% vs. 0)(P<0.0l),(100% vs.44.4%) (P<0.05)respectively than those without it in observed groups.In patients harboring EGFR mutations, disease control rate to patients treated with Iressa (100%) was significantly higher than those who never treated with it (40%)(P<0.05). The frequency distribution of EGFR intron 1 (CA)n repeat in 48 specimens was 23(47.9%)low (CA)n repeat(CA≤16)and 25 (52.1%) high repeat(CA>16). There was no significant difference in response rate and disease control rate of EGFR TKIs treatment between low and high (CA)n repeat numbers both in 16 patients with mutations and 18 patients without mutations in observed groups(P>0.05). Conclusions: Somatic mutations of EGFR is a major determinant of EGFR TKIs response in lung cancer. There was no significant difference in response rate and disease control rate of EGFR TKIs treatment between low (CA) n repeat patients and high repeat ones under the consideration of the mutant factor. No significant financial relationships to disclose.

Download Full-text

FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel: Results from the phase II RAMIRIS Study of the AIO.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4514 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4514-4514 ◽

Cited By ~ 1

Author(s):

Sylvie Lorenzen ◽

Peter C. Thuss-Patience ◽

Claudia Pauligk ◽

Eray Goekkurt ◽

Thomas Jens Ettrich ◽

...

Keyword(s):

Disease Control ◽

Phase Ii ◽

Response Rate ◽

Objective Response ◽

Disease Control Rate ◽

Phase Iii ◽

Response Analysis ◽

Second Line ◽

Significant Difference ◽

Gastroesophageal Adenocarcinoma

4514 Background: Ramucirumab (Ram) as monotherapy or plus paclitaxel is a proven second-line option for advanced gastroesophageal adenocarcinoma (GEA). More and more patients (pts) are pretreated with docetaxel in the perioperative or first-line setting. These pts may benefit more from another, non-cross resistant chemotherapy backbone regimen. This trial evaluates the addition of Ram to FOLFIRI as second line treatment. Methods: This is a multicenter, randomized, investigator initiated, phase II trial. Pts with GEA who have progressed after treatment with a fluoropyrimidine/platinum-containing regimen were randomized 2:1 to either FOLFIRI plus Ram every two weeks (Arm A) or paclitaxel (days 1, 8, 15 of a 28-day cycle) plus Ram every two weeks (Arm B). Major endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and toxicity. Results: 111 pts (median age 61 years, 65% of pts had prior docetaxel therapy) were enrolled and 110 analyzed within intention to treat population (ITT, Arm A, 72; Arm B, 38). In the ITT, there was no significant difference in median OS (A, 6.8 vs. B, 7.6 months, HR 0.94, p = 0.77) and median PFS (A, 4.6 vs. B, 3.6 months, HR 0.72, p = 0.12). For pts with prior docetaxel use (71/110), median PFS was A, 4.3 vs. B, 2.0 months, HR 0.49, p = 0.008 and median OS was A, 7.5 vs. B, 6.4 months, HR 0.71, p = 0.25. In 101 pts with tumor assessment and included in the response analysis, ORR and DCR was 23% and 65% in Arm A and 11% and 60% in Arm B, respectively. 67 pts assessable for response were pre-treated with docetaxel. In these pts, ORR was 24% in Arm A and 9% in Arm B. Disease control rate (DCR) was 67% and 41% for Arm A and B respectively. Both therapies were similarly tolerable, final safety results will be shown. Conclusions: The RAMIRIS trial demonstrated feasibility of the combination of FOLFIRI and Ram. With a response rate of 24% and a median PFS of 4.3 months, docetaxel pre-treated pts seemed to derive pronounced benefit from FOLFIRI-Ram, providing a rationale for a phase III trial, which is currently ongoing. Clinical trial information: NCT03081143 .

Download Full-text

Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Exploratory Study to Evaluate the Efficacy and Safety of HAD-B1 for Dose-Finding in EGFR Mutation Positive and Locally Advanced or Metastatic NSCLC Subjects Who Need Afatinib Therapy

Integrative Cancer Therapies ◽

10.1177/15347354211037917 ◽

2021 ◽

Vol 20 ◽

pp. 153473542110379

Author(s):

Eun-Ju Ko ◽

Eun-Bin Kwag ◽

Ji Hye Park ◽

So-Jung Park ◽

Ji-Woong Son ◽

...

Keyword(s):

Lung Cancer ◽

Disease Control ◽

Exploratory Study ◽

Egfr Mutation ◽

Test Group ◽

Disease Control Rate ◽

Efficacy And Safety ◽

Significant Difference ◽

Egfr Tki ◽

Group 1

Afatinib is a target anticancer drug of the second-generation EGFR TKI type, showing an advantage in treatment effect compared to conventional chemotherapy. However, patients on EGFR-TKI drugs also usually progress after 9 to 13 months according to secondary resistance. HAD-B1 is composed of drugs that are effective against lung cancer. This study is an exploratory study to evaluate the efficacy and safety between dosage groups by conducting a clinical trial in subjects requiring afatinib drug treatment in non-small cell lung cancer with EGFR mutation positive to determine the optimal dosage for HAD-B1 administration. At the final visit compared to before administration, each change in the disease control rate was measured according to the HAD-B1 doses of the test group 1 (972 mg), the test group 2 (1944 mg), and the control group. The efficacy and safety of HAD-B1 were compared and evaluated through sub-evaluation variables. As a result of the study, there was no statistically significant difference in the disease control rate at 12 weeks after dosing, but complete and partial remission were evaluated as 1 patient each in the test group 1, and none in the other groups. There was no statistically significant difference between groups in the sub-evaluation variable. In addition, there was no problem of safety from taking the test drug. However, the initially planned number of subjects was 66, but the number of enrolled subjects was only 14, which may limit the results of this study.

Download Full-text

A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) for patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8036 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8036-8036 ◽

Cited By ~ 10

Author(s):

Melissa Lynne Johnson ◽

Eric M Hart ◽

Alfred Rademaker ◽

Bing Bing Weitner ◽

Alexandra Urman ◽

...

Keyword(s):

Lung Cancer ◽

Phase Ii ◽

Response Rate ◽

Phase Ii Study ◽

Hsp90 Inhibitor ◽

Stage Ii ◽

Egfr Mutations ◽

Egfr Mutant ◽

Egfr T790m ◽

Egfr Tkis

8036 Background: AUY922 is a synthetic HSP90 inhibitor that degrades client onco-proteins including EGFR. Preclinical studies demonstrate HSP90 inhibitors are effective agents against models of AR in EGFR-mutant lung cancer cell lines and xenografts harboring the “gatekeeper” mutation EGFR T790M. Pts with EGFR mutations who develop AR often continue E with 2nd-line therapies to avoid “disease flare” associated with discontinuing TKI. This phase II study combines AUY922 and E for the treatment of pts with EGFR-mutant lung cancer and RECIST-progression on 1st-line EGFR TKIs. Methods: Eligible pts had EGFR mutations and developed AR (Jackman, JCO 2010) after treatment with EGFR TKIs. Pts underwent tumor biopsies after developing AR and prior to study entry. Pts received AUY922 70 mg/m2 IV weekly and E 150 mg oral daily in 28-day cycles. Response assessment occurred at 4 weeks (wks), 8 wks, and every 8 wks thereafter. The primary objective was overall response rate (ORR, CR+PR) at 8 wks. A Simon mini-max design determined sample size (stage I: 16 pts (≥2 responses needed to proceed to stage II), stage II: 9 pts; α=10%, β=10%, p0=10%, p1=30%). Tumor tissue from re-biopsy at study entry was analyzed for EGFR T790M. Results: Sixteen pts have been treated (10 women, median age 58 [range 47-76]). The median time on EGFR-TKI prior to the development of AR was 12 mo (range 2-42 mo). Seven pts had EGFR T790M confirmed by tumor re-biopsy. ORR was 2/16 (13%, 95% CI 2-37%). Both pts with PR had EGFR T790M. Four other pts had stable disease for at least 8 wks, two remain on study after more than 12 wks. Adverse events reported in ≥20% of pts were diarrhea, fatigue, myalgias, nausea, and transient flashing lights or night blindness. One pt each experienced grade 3 diarrhea and cardiac abnormalities. Conclusions: AUY922 and E is a well-tolerated regimen for pts with EGFR-mutant lung cancer and AR to EGFR TKIs. Two pts remain on study and 9 additional pts will be accrued in stage II; final response rate and survival outcomes will be reported. Supported by Novartis, Inc. Clinical trial information: NCT01259089.

Download Full-text

Treatment and Outcomes of Metastatic Non-Small-Cell Lung Cancer Harboring Uncommon EGFR Mutations: Are They Different from Those with Common EGFR Mutations?

Biology ◽

10.3390/biology9100326 ◽

2020 ◽

Vol 9 (10) ◽

pp. 326

Author(s):

Hyun Ae Jung ◽

Sehhoon Park ◽

Jong-Mu Sun ◽

Se-Hoon Lee ◽

Jin Seok Ahn ◽

...

Keyword(s):

Lung Cancer ◽

Egfr Mutation ◽

Response Rate ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

First Line ◽

Compound Mutation ◽

Egfr Tki ◽

Egfr Tkis

Approximately 10% of the epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are uncommon EGFR mutations. Although the efficacy of second (2G) or third generation (3G) EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the patients with uncommon EGFR mutation has been proven, further studies are warranted to define the optimal treatment approach for uncommon EGFR mutation-positive NSCLC. This study retrospectively investigated the treatment patterns and outcomes of patients with uncommon EGFR mutation-positive NSCLC from January 2011 to December 2019 at the Samsung Medical Center, Seoul, Korea. During the study, 2121 patients with EGFR mutation-positive NSCLC received first-generation (1G, gefitinib or erlotinib) or 2G EGFR-TKI (afatinib) as the first-line (1L) systemic therapy. Of this, 135 (6.4%) patients harbored uncommon EGFR mutations. Of 135, 54 (40%, 54/135) patients had overlapping mutations with major EGFR mutations. The objective response rate (ORR) for the 1L EGFR-TKI was 63.3%. The median progression-free survivals (PFSs) were 8.6 months (95% CI: 3.8–13.5), 11.7 months (95% CI: 6.6–16.7), 7.7 months (95% CI: 4.9–17.4), and 5.0 months (95% CI: 3.7–6.1) for major uncommon EGFR mutation (G719X, L861Q), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The median overall survivals (OSs) were 25.6 months (16.9–34.2), 28.8 (95% CI: 24.4–33.4), 13.5 months (95% CI: 7.4–27.8), and 9.4 months (95% CI: 3.4–10.5) for major uncommon EGFR mutation (G719X), compound mutation with major EGFR mutation (Del 19 or EGFR exon 21 p.L858R), other compound mutation, and other uncommon mutations, respectively. The response rate, median PFS, and OS were 63.3%, 16.3 months (95% CI: 15.6–16.9), and 37.5 months (95% CI: 35.4–39.6) for common EGFR mutation-positive NSCLC. After failing 1L EGFR-TKI, repeated tissue or liquid biopsy were carried out on 44.9% (35/78) of patients with T790M detected in 10/35 (28.6%) patients. With subsequent 3G EGFR-TKI after failing the first-line EGFR-TKI, the ORR and PFS for 3G EGFR-TKI were 80% and 8.9 months (95% CI: 8.0–9.8). These patients showed a median OS of 34.6 months (95% CI: 29.8–39.4). The ORR, PFS and OS were poorer in patients with uncommon (especially other compound and other uncommon mutation) than those with common EGFR mutations. T790M was detected in 28.6% of the uncommon EGFR mutation-positive patients for whom prior 1G/2G EGFR-TKIs failed and underwent repeat biopsy at the time of progression.

Download Full-text

Effectiveness of treatment with endostatin in combination with emcitabine, carboplatin, and gemcitabine in patients with advanced non-small cell lung cancer: a retrospective study

Open Medicine ◽

10.1515/med-2018-0022 ◽

2018 ◽

Vol 13 (1) ◽

pp. 142-147

Author(s):

Xun Yu ◽

Lemeng Zhang ◽

Jianhua Chen

Keyword(s):

Lung Cancer ◽

Adverse Events ◽

Disease Control ◽

Clinical Efficacy ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Disease Control Rate ◽

Combination Group ◽

Chemotherapy Group ◽

Significant Difference

AbstractThis study investigated the clinical efficacy, safety and tolerance of endostatin combined with gemcitabine and carboplatin for patients with advanced nonsmall cell lung cancer (NSCLC).From January 2010 to January 2014, 49 patients with advanced NSCLC were retrospectively evaluated; we defined 2 subgroups: a combination group (chemotherapy + anti-angiogenic therapy) and a chemotherapy group (chemotherapy only). The cases in the chemotherapy group received treatment with gemcitabine and carboplatin only, whereas the cases in the combination group received endostatin in combination with gemcitabine and carboplatin. The patients received 2 cycles of treatment (21 days/cycle). The clinical efficacy and adverse events were observed and compared.The disease control rate in the combination group was significantly higher compared with the chemotherapy group (P < 0.05). When comparing the cases of squamous carcinoma, the disease control rate in the combination group was significantly higher than the chemotherapy group (P < 0.05). Moreover, the progression free survival in the combination group was higher than that for the chemotherapy group, with a statistically significant difference (P < 0.05).The combination of endostatin with chemotherapeutic agents is improve to the survival of patients with advanced NSCLC favorably; the adverse events of this regimen are well tolerated.

Download Full-text

High-resolution melting analysis (HRMA) for KRAS mutational study in patients with metastatic colorectal cancer (mCRC pts).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.515 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 515-515 ◽

Cited By ~ 1

Author(s):

Alfonso De Stefano ◽

Umberto Malapelle ◽

Chiara Carlomagno ◽

Roberto Bianco ◽

Roberta Marciano ◽

...

Keyword(s):

Disease Control ◽

Stable Disease ◽

Response Rate ◽

Direct Sequencing ◽

Disease Control Rate ◽

Therapeutic Effects ◽

Combination Regimen ◽

Kras Status ◽

Significant Difference ◽

Third Line

515 Background: The use of anti EGFR monoclonal antibodies cetuximab and panitumumab is restricted to KRAS wild-type (WT) mCRC pts. Standard method for KRAS testing is direct sequencing. To overcome its limited sensitivity, novel techniques have been developed. However there is little concordance on the clinical significance of more sensitive tests. HRMA is very sensitive and economic and allows rapid detection of DNA sequence variations based on specific sequence-related melting profile. Here we report the evaluation of therapeutic effects of cetuximab in direct sequencing tested WT pts, according to their HRMA mutational status. Methods: We retrospectively evaluated 50 (35 males, 15 females) mCRC pts with WT KRAS status by direct sequencing. Median age was 61 years (range 29 – 77). Most (40%) pts had liver metastases and 24% had multi-organ disease. They received second- or third-line cetuximab-containing chemotherapy, with irinotecan (n=25) or with combination regimen (22 FOLFIRI and 3 FOLFOX). Twenty-eight pts were treated in second-line and 22 in third-line. KRAS mutation status was reassessed in all pts using HRMA. Results: All 50 pts were evaluated for tumor response, PFS and OS. In 4 (8%) pts, KRAS mutations were only identified by HRMA. The response rate of HRMA KRAS WT pts was 28.3%, with 1 complete (2.2%) and 12 partial (26.1%). No response was observed in HRMA KRAS MT (3/4 with a progression as best response). Stable disease rates were 30.4% (14/46 pts) and 25% (1/4 pts) in HRMA WT and MT cases respectively. Disease control rate (objective responses plus stable disease) was 58.7% in HRMA KRAS WT pts and 25% in HRMA KRAS MT. No significant correlation was found between HRMA-KRAS status and response rate (p=0.287) or disease control rate (p=0.219). However, median PFS (5.1 versus 2.5 months; HR=0.34, p=0.04) and median OS (11.3 versus 3.2 months; HR=0.11, p=0.03) were significantly longer for HRMA KRAS WT pts compared to HRMA KRAS MT. Conclusions: These data show a significant difference in clinical outcome between HRMA KRAS WT and MT pts receiving a cetuximab-containing second- or third-line treatment, suggesting that techniques more sensitive than direct sequencing could better select pts for cetuximab-based treatment.

Download Full-text

Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190902150555 ◽

2019 ◽

Vol 19 (23) ◽

pp. 2128-2142 ◽

Cited By ~ 2

Author(s):

Hao He ◽

Chang Xu ◽

Zhao Cheng ◽

Xiaoying Qian ◽

Lei Zheng

Keyword(s):

Lung Cancer ◽

Adjuvant Therapy ◽

Combination Therapy ◽

Clinical Benefit ◽

Poor Prognosis ◽

Egfr Mutations ◽

Kras Mutations ◽

Lung Cancers ◽

Egfr Tki ◽

Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Download Full-text