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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Osimertinib is an EGFR TKI that is active against T790M, the most common resistance mutation seen in patients who have progressed following first line EGFR-TKI therapy. In a phase I/II study of 253 patients who had progressed on an EGFR-TKI, osimertinib demonstrated a response rate of 51% [28]. Among 127 patients with a confirmed EGFR T790M, the response rate was 61%. The median progression-free survival was 9.6 months in EGFR T790M-positive patients. The benefit of osimertinib in EGFRT790M positive lung cancer was confirmed in a phase III trial against chemotherapy following first-line EGFR TKI therapy [29]. In this trial of 419 patients, osimertinib had a PFS of 10.1 months vs. 4.4 months with platinum-pemetrexed (HR 0.30; 95% CI 0.23 to 0.41; P<0.001). The corresponding response rates were 71% and 31%, respectively. In a phase III trial in treatment naïve patients with activating EGFR mutations, osimertinib had a superior PFS compared to standard of care TKIs (18.9 vs. 10.2 months; HR 0.46 (0.37, 0.57); p<0.0001)
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Brigatinib has also been shown to selectively inhibit mutated EGFR, which is helpful from a clinical perspective as it is also a validated target for NSCLC. For example, it is known that the T790M “gatekeeper” EGFR mutation is present in approximately 50% of patients who become resistant to first-generation EGFR inhibitors. While second-generation EGFR inhibitors have been developed, clinical efficacy is often limited due to toxicities associated with inhibiting the native (endogenous or unmutated) EGFR. Therefore, a therapy targeting the T790M mutation of EGFR while avoiding inhibition of native EGFR is useful. It has also been established that brigatinib can overcome resistance to osimertinib (TagrissoTM; see Section 6.2.1.6.5) conferred by the EGFR C797S mutation if it is combined with an anti-EGFR antibody such as cetuximab or panitumumab.
Predictive Biomarkers for Epidermal Growth Factor Receptor Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Penelope Bradbury, John Hilton, Janet E. Dancey
AECHER 1050 was a phase III trial of dacomitinib versus gefitinib and was the first trial to directly compare EGFR TKIs in patients with advanced or metastatic EGFR exon 19 deletion or L858R positive NSCLC, with or without T790M mutation positive NSCLC (Mok, 2018). The primary endpoint of progression-free survival was met with median of 14.7 months for dacomitinib versus 9.2 months for gefitinib (HR 0.59 (95% CI 0.47–0.74), p < 0.0001). This benefit was at the cost of greater toxicity, characteristic of the second-generation EGFR TKIs, with increased grade 3 adverse events (30% versus 5%), predominantly diarrhea, paronychia and other skin toxicities, although gefitinib was associated with more liver function test abnormalities. Diarrhea was the most common adverse event for both EGFR-TKIs but the frequency and grade were higher with dacomitinib compared to gefitinib. In a follow-up analysis for OS when data was mature with a median follow-up of 31.3 months, the median overall survival on the dacomitinib arm was 34.1 months versus 26.8 months (HR 0.760 (95%CI 0.582–0.993); p = 0.044 (Mok, 2018), and was the first agent to show an overall survival advantage in this population. Again, like the first-generation EGFR TKIs, disease relapsed, and the predominant mechanism of acquired resistance was the emergence of T790M mutation.
Targeting the EGFR signaling pathway in cancer therapy: What’s new in 2023?
Published in Expert Opinion on Therapeutic Targets, 2023
Sushanta Halder, Soumi Basu, Shobhit P. Lall, Apar K. Ganti, Surinder K. Batra, Parthasarathy Seshacharyulu
Based on the earlier clinical trials, it is predicted that EGFR TKI’s effectiveness is primarily based on the presence or absence of activating EGFR tyrosine kinase (TK) mutations in patients with lung cancer. These acquired EGFR mutations will occur after 9–14 months of treatment initiation. EGFR-positive and nonsmokers had significant survival benefits upon erlotinib treatment. Similarly, gefitinib’s clinical response is good in female patients with a history of nonsmoking habits. Later, it was identified that EGFR-TKI’s effectiveness is higher in females (gender) and Asian origin (ethnicity) due to more participation of Asian women with EGFR TK mutation-positive NSCLC patients. A major limitation of EGFR-TKI is the Starting from first-generation erlotinib (T790M), second-generation Afatinib, and third-generation osimertinib (L858R/T790M/C797S or Del19/T790M/C797S) were shown to induce acquired EGFR mutations. Hence, all these EGFR family members targeting agents exhibited modest benefits in clinical settings to cancer patients. 50% of cancer patients will show acquired EGFR mutation at T790M in EGFR. Thus, there is a critical need to progress toward identifying and validating EGFR mutant-specific EGFR-TKIs without causing additional mutations. Some of the acquired mutations are the same in two different cancers. For e.g. EGFR mutations at exon 21 (L858R) and exon 19 (deletion) are also observed among TNBC (although rare) like NSCLC patients. In such cases, the newly identified compounds should be evaluated regardless of cancer and its subtype.
An evaluation of aumolertinib for the treatment of EGFR T790M mutation-positive non-small cell lung cancer
Published in Expert Opinion on Pharmacotherapy, 2022
Aumolertinib’s chemical formula is N-[5-[[4-(1-cyclopropylindol-3-yl)-pyrimidin-2-yl]amino]-2-[2-(dimethylamino)ethyl-methylamino]-4-methoxyphenyl]prop-2-enamide. Aumolertinib is similar to other third-generation EGFR-TKIs. Aminopyrimidine is used as their core, while the Michael addition receptor is introduced. Based on this structural foundation, aumolertinib can interact with and irreversibly bind to cysteine-797 (Cys797) through an unsaturated acrylamide bond at the ATP binding site of the EGFR tyrosine kinase domain. Thus, it can selectively act on EGFR-sensitive mutations and EGFR T790M-resistant mutation. Aumolertinib is optimized based on the structure of osimertinib, in which the methyl group is replaced with a cyclopropyl group on the indole nitrogen ring [14,15]. Cyclopropyl group has been shown to improve the metabolic stability and receptor subtype selectivity of aumolertinib, while avoiding the production of nonselective metabolites that strongly inhibit wild-type EGFR (WT-EGFR) during drug metabolism. Meanwhile, the addition of cyclopropyl group increases the blood-brain barrier permeability of aumolertinib [16].
Cost-effectiveness analysis of osimertinib for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small cell lung cancer in Singapore
Published in Journal of Medical Economics, 2020
Mohamed Ismail Abdul Aziz, Wayne Yong Xiang Foo, Chee Keong Toh, Wan-Teck Lim, Kwong Ng
The model compared two treatment arms in a population of locally advanced or metastatic NSCLC patients with EGFR mutation. In the osimertinib arm, patients first receive osimertinib (80 mg daily; first-line), followed by platinum doublet chemotherapy (pemetrexed-cisplatin or pemetrexed-carboplatin; second-line), chemotherapy/immunotherapy (docetaxel, pembrolizumab, or nivolumab; third-line), and then best supportive care (BSC). In the standard EGFR TKI arm, patients receive erlotinib (150 mg daily) or gefinitib (250 mg daily) as first-line treatment. After progression, treatment strategies differed based on T790M status. For T790M-positive patients, they will receive osimertinib (second-line), platinum doublet chemotherapy (pemetrexed-cisplatin or pemetrexed-carboplatin; third-line), followed by BSC. T790M-negative patients will receive platinum doublet chemotherapy (pemetrexed-cisplatin or pemetrexed-carboplatin; second-line), chemotherapy/immunotherapy (docetaxel, pembrolizumab, or nivolumab), and then followed by BSC. The treatment strategies were reflective of the local clinical practice in the management of EGFR mutant NSCLC patients in Singapore, after consultation with local clinical experts. An overview of the treatment algorithm is depicted in Figure 2.