They share a mutation, that of the Ret gene (Rearranged during transfection) and the fact that they are rare: two characteristics have made – up to now – more difficult to find effective therapeutic solutions. These are advanced non-small cell lung cancers (NSCLC), advanced or metastatic thyroid cancer, and medullary thyroid cancer (MTC). Today, however, there is a chance for patients with these cancers: after the Food and Drug Administration and the EMA, our Medicines Agency (Aifa) last month granted the marketing authorization of selpercatinib as second-line monotherapy.
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Rare tumors and genomic profiling
The alteration of the RET gene is estimated to have an incidence of about 2% in lung cancer, about 10% in thyroid tumors and about 50% in medullary thyroid tumors. Genetic mutations in tumors change the therapeutic approach, shifting the focus from the tissue study of the tumor to its genomic profiling. “Over time, non-small cell lung cancer has become the perfect example of the application of precision medicine in oncology – he explains Silvia Novello, Professor of Medical Oncology at the University of Turin and president of WALCE Onlus (Women Against Lung Cancer in Europe / Women against lung cancer in Europe). A third of the patients diagnosed with this metastatic cancer are carriers of a cancer characterized by a genetic alteration and can be treated with a specific drug and 2% have an alteration of RET, which is the specific target of this first newly approved drug “.
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Papillary thyroid and medullary carcinoma
Same reasoning for papillary thyroid cancer (PTC). “It is a rare tumor and fortunately in 90% of cases it has a favorable prognosis – he observes Rossella Elisei, Associate Professor of Endocrinology and Medical Director of the Endocrinology Unit and Experimental Clinical Medicine, AOU Pisana. Some, however, may present already advanced and over time may require systemic therapy for distant metastases. 10-20% of these have a genetic alteration of the RET oncogene, a chromosomal rearrangement, which is the cause ”. The same RET oncogene is also mutated in 50% of another type of thyroid cancer, medullary carcinoma (MTC), which is more aggressive than PTC and frequently requires therapy for metastatic disease. “The evidence that the pathogenesis of these tumors is due to an alteration of the RET oncogene has led to the development of drugs capable of deactivating this gene”, he continues Elisei. “Selpercatinib is a specific, effective and well tolerated RET inhibitor. In patients treated with this drug, the disease does not disappear, but becomes chronic, allowing them to lead their lives without particular limitations. We hope that this therapeutic approach, a typical example of precision medicine, can extend to other types of cancer, certainly the path that the research is taking is precisely this “.
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A personalized therapy
Selpercatinib is an example of precision medicine and personalized therapy, as it is a selective and potent inhibitor that blocks proliferative activity, due to the alteration of the RET gene and causes tumor growth arrest with moderate side effects. The reference study (LIBRETTO-001), which led to the approval of selpercatinib, is the largest clinical study in patients with tumors with alteration of the RET gene treated with a specific inhibitor for this alteration, a study involving 16 countries and 89 research centers. The results showed an objective response rate of 61% in pretreated NSCLC patients, 79% in pretreated thyroid cancer patients and 69% in pretreated MTC patients. The study continues to enroll patients with other RET-altered cancers, in addition to those with lung, thyroid and medullary cancers. As for side effects, selpercatinib is associated with the occurrence of predominantly low-grade toxicity; the most common adverse events were dry mouth, diarrhea, hypertension, ALT / AST elevation, peripheral edema, constipation, rash, headache and fatigue.