What is adenocarcinoma lung cancer

Two relatively new drugs for first-line and second-line therapy signal hope for patients with advanced, non-small cell adenocarcinoma of the lung with and without EGFR mutation: afatinib and nintedanib. A genetic analysis is a prerequisite for first-line therapy.

In Germany, lung cancer is by far the most common cause of cancer death in men (25%) and the third most common in women (15%), but the incidence rate is rising steadily among women. The 5-year survival rate is 16% for men and 21% for women. Only in recent years has it been recognized that molecular genetic factors play an important role in the genesis of NSCLC: In around 50% of adenocarcinomas, driver mutations can be detected in genes that are potentially important for malignant transformation: KRAS (22%), EGFR (17%) EML4-ALK (7%), BRAF, PIK3CA, HER2 or AKT1, i.e. H. Not only the histological subtype but also genetic differences influence the response to therapy. This is why new therapeutic agents target the modified proteins, such as afatinib (Giotrif®) against EGF receptors and nintedanib (Vargatef®) against various receptors that are important for angiogenesis.

Mutation testing required before afatinib

Up to 17% of patients with lung adenocarcinoma have a mutated receptor for epidermal growth factor (EGFR), which, according to Niels Reinmuth, Großhansdorf, is largely responsible for the development of lung cancer, especially in women and infrequent smokers. A prerequisite for a targeted first-line therapy with afatinib is therefore a test for the presence of mutations in the EGFR gene, emphasized the pathologist Markus Falk, Hamburg. In addition to EGFR, inter alia tested for ALK and ROS1 mutations, as it is not responsible for withholding therapy with an inhibitor directed against the respective tyrosine kinases to patients with such mutations. However, the rate of testing for EGFR mutations in patients with advanced NSCLC is currently only 72%. Around 35% start first-line therapy without a test result, for example because there is too little tissue, the patient is in poor condition or because the waiting time until the test result is too long. According to Falk, however, the waiting time can be reduced to a minimum if oncologists, pulmonologists and pathologists coordinate and organize themselves well.

This is particularly important for patients with NSCLC and frequently occurring EGFRA mutations (Del19 / L858R), which are present in 89% of cases: Afatinib almost doubled the survival benefit of these patients to 13.6 months compared to standard chemotherapy with cisplatin / Pemetrexed (6.9 months), as shown in the LUX-Lung 3 phase III study. The irreversible ErbB family blocker Afatinib, which directly and indirectly inhibits signal transmission via the receptors of the ErbB family, has been approved for first-line therapy in NSCLC with activating EGFRA mutations since 2013. In addition, in LUX-Lung 3 and LUX-Lung 6, the Asian registration study, a pre-specified subgroup analysis for patients with a deletion 19 showed a survival advantage of over twelve months compared to chemotherapy (LUX-Lung 3: 33, 3 vs. 21.1 months; LUX-Lung 6: 31.4 vs. 18.4 months). A post-hoc analysis of LUX-Lung 3 presented at the ASCO Congress 2015 also suggests that the effectiveness in terms of progression-free survival is maintained even after a dose reduction required due to side effects.

Based on the results of the Phase III LUX-Lung 8 study, the approval applications for afatinib for the treatment of patients with advanced, non-small cell squamous cell carcinoma (SCC) of the lung after failure of the first-line chemotherapy have now been submitted - due to a significant advantage in progression-free survival.

Nintedanib as a second-line therapy extends survival time

According to David Heigener, Großhansdorf, the focus in second-line therapy after failure of first-line chemotherapy in NSCLC patients is on improving quality of life, pain symptoms and tolerability. For the first time in ten years, the oral, triple-targeted angiokinase inhibitor nintedanib in combination with docetaxel also increased overall survival compared to docetaxel monotherapy. In the phase III study LUME-Lung 1, the 1,314 patients randomly received either nintedanib orally 2 x 200 mg / day plus docetaxel 75 mg / m2 i.p. v. every three weeks or placebo plus docetaxel. The combination with the angiokinase inhibitor increased overall survival from 10.3 to 12.6 months. It allows one in four patients with advanced adenocarcinoma to survive two years or more after first-line chemotherapy.

Phase III studies with nintedanib are also ongoing in refractory colorectal and ovarian cancer. It is currently being evaluated in phase II studies in malignant pleural mesothelioma, renal cell carcinoma and hepatocellular carcinoma.
The quality of life of NSCLC patients can be maintained with the well-tolerated nintedanib; somewhat more frequent side effects such as diarrhea and increased liver enzyme levels can be compensated for by supportive therapies or dose reductions.

Helga Vollmer


Meet the Clinic: "Treatment of NSCLC patients (stage IIIb / IV) with and without treatable mutations" on 10./11. August 2015 in Großhansdorf, organized by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim.