It is called amivantamab and is a monoclonal antibody that promises to change therapies for the treatment of certain types of non-small cell lung cancer (Nsclc) with the mutated Egfr gene. These are not simple predictions. At Esmo23, the European Society of Medical Oncology congress held in Madrid, the results of three important clinical studies were presented which show how the use of combination therapies with amivantamab bring significant clinical benefits.
Go beyond the tumor’s resistance
One of the most relevant clinical problems in the treatment of non-small cell lung cancers with mutated Egfr in advanced/metastatic stages is the onset of drug resistance after standard first-line therapy (osimertinib). These are currently responded to with chemotherapy, but the results are not satisfactory. “There is an extreme need for valid therapeutic options” – pointed out Antonio Passaro, oncologist at the European Institute of Oncology (Ieo) in Milan, who at Esmo23 presented the results of the Mariposa-2 study, which evaluated the safety and the efficacy of the combination of amivantamab and chemotherapy (with or without lazertinib, a third-generation tyrosine kinase inhibitor) in second line compared to chemotherapy alone in patients with common Egfr gene mutations.
by Dario Rubino
“Amivantamab is a bispecific monoclonal antibody that interferes with mutations of the Egfr and Met genes, among the main causes of the onset of resistance to standard therapy – explained Passaro – The use of amivantamab in this context is innovative and, as demonstrated data, brings significant clinical benefits to our patients. From this point of view it is a historical experiment.”
Mariposa-2 involved 657 patients divided into three experimental arms: one intended to receive chemotherapy alone (the current standard), one the combination of amivantamab and chemotherapy and one the combination of amivantamab, chemotherapy and lazertimib. The primary objective was the evaluation of disease progression-free survival in the two experimental arms compared to the control group treated with chemotherapy alone. “The risk of progression or death during the study period was reduced by more than 50% – said the doctor, who underlined another surprising fact relating to one of the secondary objectives of the trial. “In addition to very positive data on the response rate and duration of response to combinations with amivantamab, we have highlighted a clear advantage in terms of progression of intracranial disease.” Many patients with this type of neoplasm, in fact, develop brain metastases which aggravate the overall picture and worsen the prognosis. “The new protocol allows us to extend the time free from progression of intracranial disease in all patients: a result never achieved before” – underlined Passaro. Safety and toxicity data are also positive. “The balance between clinical benefits and adverse effects allows us to say that the combination of amivantamab and chemotherapy – without lazertimib, which instead has shown some additional toxicity – can aspire to become the new standard of care, after the failure of first-line therapy ”.
Alternatives also on the front line
At Esmo23, the good news for patients with advanced Nsclc with common Egfr mutations and for their doctors does not end: amivantamab, in combination with lazertinib, has given significant clinical benefits even in the first line. The Mariposa study compared this experimental strategy with the current standard of care (osimertinib) revealing a 30% reduction in the risk of disease progression or death. The Mariposa study also evaluated intracranial disease progression and the data once again indicate a clear advantage of the combination of amivantamab and lazertinib compared to osimertinib. The duration of progression-free survival and the favorable trend in overall survival observed in the study suggest that the combination of amivantamab and lazertinib has the potential to become the new standard of care in the front line of Egfr-mutated NSCLC.
Finally, in the Papillon study amivantamab proved effective in combination with traditional front-line chemotherapy in a particular population of patients affected by advanced-stage Nsclc with uncommon mutations in the Egfr gene. This is a different disease: it is poorly responsive to treatments with approved tyrosine kinase inhibitors and tends to progress rapidly; therefore, the prognosis is worse than for tumors with common Egfr mutations. The trial showed that amivantamab combined with chemotherapy reduces the risk of disease progression or death by 60% compared to chemotherapy alone. 18 months after the start of treatment, 31% of patients are free from disease progression, compared to 3% of those who undergo chemotherapy alone.
“The entry of amivantamab heralds the beginning of a new era for patients with Egfr mutated lung cancer. We see great progress both on the front line, where therapeutic options are increasing, and in the treatment of drug resistance, where the use of antibody-conjugated drugs is also being evaluated – concluded Passaro – In addition to this, we have many biological possibilities driven by mechanisms of resistance, which need to be monitored through tissue or liquid biopsies, which gives us hope for the future of our patients”.