The era of individualized therapy for non-small cell lung cancer (NSCLC) has been named for a long time until recent years, when more and more research results have continued to confirm the importance of precision targeted therapy for prolonging survival of patients with advanced NSCLC. Among them, although the ALK gene mutation rate only accounts for 5%, the overall population is huge with about 35,000 new cases in China every year, so a small gene has a big role. Previously, for stage IV lung cancer patients, the median survival time after chemotherapy alone was only about 8-10 months, but its toxic side effects were deeply feared by many patients; while for ALK-positive stage IV non-small cell lung cancer patients, using the concept of precision therapy, its line test to determine the target, the first generation inhibitor crizotinib combined with the second generation of cretinoin sequential treatment, the median survival time of this group of patients can reach 49.4 months, up to 4 years, with good tolerability, truly prolonging the survival of patients significantly. In just 4 years since the launch of the first generation inhibitor crizotinib in 2011, the overall survival of ALK-positive lung cancer patients has been greatly improved through precise detection and precise treatment, and precision therapy based on ALK fusion gene is moving toward the goal of turning tumors into chronic diseases. In this article, we will review the knowledge about ALK fusion gene in NSCLC.
I. The foundation of “other’s stone”
The ALK gene was not initially discovered in lung cancer, but was first identified in the form of an ALK fusion gene in mesenchymal large cell lymphoma 20 years ago, and was used as a marker to localize a subtype of lymphoma. It was not until 2007 when Japanese scholar Soda et al. discovered ALK gene and EML4 fusion in the tumor tissue of a smoking lung adenocarcinoma patient and confirmed it as a mutated gene with tumorigenic properties that the road to precise treatment with ALK fusion gene began. The current study found that the incidence of ALK gene rearrangement in patients with non-small cell lung cancer is about 2% to 5%, mainly in patients with lung adenocarcinoma, while the incidence is lower in squamous cell carcinoma (<1%). Moreover, the findings showed a higher incidence in patients with light smoking (≤10 packs/year) or no smoking history, and in younger patients (≤50 years). And in terms of gender, previous studies suggest that female patients may have a higher mutation rate, but currently no significant difference is considered overall. As for the value of the gene on the prognosis of the disease in this province is currently inconclusive.
Second, “test first, medication later” of the test
From clinical research results to treatment standard, as thoracic oncologists, we must realize that the trend of advanced NSCLC treatment is the precision targeted therapy of “testing first, drug later”. We need to test, not guess.
ALK fusion gene testing is mainly performed on surgical specimens, CT-guided biopsies, fiberoptic bronchoscopy biopsies, and pleural fluid cell-embedded tissues. These methods are available in most hospital pathology departments and are convenient, fast and inexpensive. However, the popular peripheral blood ctDNA and CTC cannot be used for the detection of this gene yet. In clinical practice, the three major guidelines, “Chinese guidelines for the diagnosis and treatment of epidermal growth factor receptor-sensitive gene mutation and mesenchymal lymphoma kinase-positive NSCLC”, “Chinese expert consensus on the diagnosis of mesenchymal lymphoma kinase fusion gene-positive NSCLC”, and “expert consensus on the analysis of targeted therapy for advanced NSCLC”, currently recommend the use of IHC testing for screening and concomitant diagnosis of ALK fusion gene-positive NSCLC. patients for screening and concomitant diagnosis.
Crizotinib
In 2011, the US Food and Drug Administration approved crizotinib for the treatment of ALK gene rearrangement-positive advanced NSCLC. Crizotinib is an oral formulation that is highly specific and can efficiently inhibit the autophosphorylation of ALK gene to inhibit tumor cell growth. The recommended dose of crizotinib capsules is 250 mg orally twice daily until disease progression or intolerable to the patient. Also for patients with severe renal impairment without dialysis (creatinine clearance <30 ml/min), the recommended dose is 250 mg/day orally. Capsules should be. Crizotinib capsules are swallowed whole with or without food. If a dose is missed, the missed dose may be made up, but only if it is longer than 6 hours before the next dose. Dose adjustments may also be made based on toxicities in treatment.
The PROFILE1007 study, published in June 2014 in the New England Journal of Medicine, showed that the median survival time in the crizotinib group was 7.7 months compared to 3.0 months in the docetaxel or pemetrexed groups in second-line treatment of patients with non-small cell lung cancer, and that patients treated with crizotinib had a higher quality of life and longer recurrence-free survival. It was confirmed that second-line treatment in ALK-positive advanced non-small cell lung cancer was significantly superior to conventional chemotherapy.
In the PROFILE 1014 study, also published in the New England Journal of Medicine in December 2014, crizotinib was significantly superior to chemotherapy in ALK-positive non-squamous non-small cell lung cancer, with an objective efficacy rate of 74% versus 45%, equivalent to significant tumor shrinkage in 3/4 of patients, and a progression-free survival time of 10.9 months versus 7.0 months, confirming significant improvement in first-line treatment of ALK-positive advanced non-small The first-line treatment of ALK-positive advanced non-small cell lung cancer is significantly better than conventional chemotherapy. Therefore, it is currently believed that taking targeted therapeutic agents can extend the median survival from 7.4-8.1 months to 3.5 years, in other words, most patients can obtain more than 1 year of survival extension, which is clinically significant, and current guidelines recommend crizotinib as the first-line treatment option for ALK-positive non-small cell lung cancer. In an article published in another prestigious journal in 2015, the first-generation inhibitor crizotinib combined with the second-generation cretinoin in sequential therapy resulted in a median overall survival time of 49.4 months, more than 4 years, opening a new milestone for true precision therapy.
The Journal of Clinical Oncology published online in January 2015 a retrospective analysis of the PROFILE 1005 and 1007 studies found that ALK-positive non-small cell lung cancer patients with brain metastases after treatment with an ALK inhibitor were still treated with crizotinib. remained effective after treatment with crizotinib. Therefore, it is currently recommended to continue crizotinib treatment after progression of intracranial lesions, and patients may still benefit.
4. Toxic effects of “white jade”
As an oral agent, studies have shown that crizotinib is well tolerated. Most of the adverse reactions of crizotinib in clinical practice are in the range of 1 to 2 degrees, which are both tolerable and a few require treatment, including visual effects such as blurred vision, mosquitoes, photophobia, diplopia, etc.; gastrointestinal reactions such as nausea, vomiting, diarrhea and constipation. Occasionally, adverse reactions are in the 3rd to 4th degree, mainly leukopenia, elevated transaminases, hypophosphatemia, etc. After active clinical treatment, most of them can obtain good regression.
V. “promising” drug resistance
Almost all TKIs have drug resistance problems at 9-12 months after initial treatment. Drug resistance has become the most common and biggest obstacle to the clinical application of TKIs, and is also the most urgent problem to improve the survival time of patients with advanced NSCLC. For patients with ALK+ NSCLC, the clinical benefit is clear, but this group of patients often develops resistance to crizotinib within 1 – 2 years, and relapse progression in the central nervous system is more common is
Current studies suggest that the mechanisms of resistance after crizotinib treatment are.
1, ALK secondary resistance mutations, about 37% of drug resistance is attributed to ALK secondary resistance mutations.
2, driver gene conversion, ALK+ tumor cells mainly through ALK and its downstream signaling pathways to control the growth and migration of tumor cells, both other tumor driver gene activation.
3, tumor heterogeneity NSCLC is one of the tumors with the greatest genetic and cellular heterogeneity, and its tumor cells may have different driver gene mutations at different times and in different spaces.
Therefore, what about drug resistance? Currently, the commonly used treatment strategies after crizotinib resistance are.
1, second generation ALK inhibitors (Alectinib, Ceritinib, AP26113) capable of inhibiting ALK secondary resistance mutations.
2, combination of other therapies, application of ALK inhibitors and other signaling pathway inhibitors that have the potential to improve such mechanisms leading to resistance, including combination of heat shock protein inhibitors, combination of other inhibitors such as EGFR previous studies, combination of chemotherapy, etc..
3, continue crizotinib treatment, a very important point is that this resistance is often incomplete, so when the disease progresses, for patients with NSCLC who have acquired resistance to targeted drug therapy, there are still some tumor cells that can continue to be inhibited by targeted drugs, especially when intracranial tumors progress, patients can still benefit from continued use.
Sixth, the “careful calculation” of the gift of drugs
At present, these drugs are expensive, and the related charity drug donation program can relieve the financial pressure of some patients. The assistance program is administered by China Cancer Foundation, and the target of the assistance is poor and low-income oncology patients who meet the medical criteria of the program.
The assistance program includes two phases, Phase I and Phase II. Assistance program.
Phase I: In the first year, patients who have taken Seconal for 4 treatment cycles (4 bottles), confirmed to be safe and effective with no serious side effects, will enter the follow-up visit to receive the drug after the project office has reviewed and approved, and can receive 8 treatment cycles of the donated drug (up to 8 bottles).
Phase II: After the end of Phase I donation, patients who are assessed by the designated physician of the project to still need to continue treatment with Cytomel and have the intention to apply, the second year patients take Cytomel for 2 treatment cycles (2 bottles), and donate until the end of treatment after review and approval by the project office. Patients using this drug can contact their local registered physicians or directly consult the China Cancer Fund and related organizations.
VII. Conclusion.
The purpose of oncology treatment is to prolong patients’ survival time and improve their quality of life. Oral agents are well tolerated, and precision therapy has led to an overall survival time of more than 4 years for ALK-positive patients with advanced lung cancer. However, there are still relevant issues, including the detection method of EMI4-ALK fusion gene still needs to be improved to enhance its specificity and sensitivity of detection, problems related to crizotinib resistance, etc. The past experience of patient treatment tells us that the key to precision therapy is to “test first, then use drugs”, and to really clarify the heterogeneity of the tumor before targeting therapy, which is also our principle for other targeted therapies in the future.