Afatinib Demonstrates Manageable Toxicity, Promising Efficacy in TKI-Naive Patients With EGFR+ NSCLC

lung cancer

According to results from a phase IIIb interim analysis, afatinib (Gilotrif) demonstrated a predictable and manageable toxicity profile and promising efficacy in patients withEGFRmutation-positive non—small cell lung cancer (NSCLC). The findings were consistent with data from the LUX-Lung (LL) 3/6 trials that compared frontline afatinib to standard chemotherapy in the same patient population.

In the LL 3/6 trials, patients with NSCLC and anEGFRmutation were treated with first-line afatinib compared with chemotherapy, which led to a significantly improved progression-free survival (PFS). The median PFS in patients that received the EGFR tyrosine kinase inhibitor (TKI) was 11.1 months compared with 6.9 months with chemotherapy.

In the phase IIIb study, presented during the 2019 European Lung Cancer Congress, patients with locally advanced or metastaticEGFR-positive NSCLC with an ECOG performance status (PS) of 0-2 who had not previously received an EGFR TKI were randomized to receive 40 mg/day of afatinib. The primary endpoint was adverse events (AEs). In addition, investigators also assessed efficacy.

Overall, 479 patients were evaluated with a median duration of treatment of 359 days, of which 258 (54%) patients received a dose reduction due to AEs. Treatment was discontinued due to AEs in 105 (22%) patients. The most frequent AEs included diarrhea. Only 39 (8%) patients experienced afatinib-related serious AEs.

The median PFS for all patients in the phase IIIb trial at interim analysis was 13.4 months (11.8—14.5). However, patients with an ECOG PS 2 or an uncommon mutation had a median PFS of 6.2 and 6.0 months, respectively. Exon 20 accounted for 80% of the uncommon mutations, which are known to be resistant to EGFR TKIs.

In an interview withTargeted Oncology, Antonio Passaro, MD, PhD, a medical oncologist and thoracic oncologist at the European Institute of Oncology, Milan, Italy, discussed the findings from this phase IIIb trial for patients withEGFRmutation-positive NSCLC. In addition, he highlighted results from other clinical trials investigatingALKandKRASmutations in patients with NSCLC.

TARGETED ONCOLOGY:Can you start by discussing the interim findings from the phase IIIb trial of afatinib in patients withEGFR-positive NSCLC?

Passaro:This is a very interesting analysis. We are happy to find the results in the randomized clinical trial had very stringent inclusion criteria. In this phase IIIb, we evaluated the 479 patients that received afatinib in the first-line setting forEGFR-positive NSCLC. We included patients with ECOG PS 0, 1, and 2, patients with brain metastases, and patients with common and uncommon mutations. This is a very heterogenous patient population that reflected the real-world clinical practice.

Overall survival (OS) overlapped the data of the randomized clinical trials, LUX-Lung 3 and LUX-Lung 6. We have a PFS of more than 13 months. The time to symptomatic progression was 14.9 months, which was approximately 50 days more. For patients with an ECOG PS2 or patients with an uncommon mutation that received afatinib in the third-line setting, the PFS was 6 months, enough of the PFS of the overall patient population. It is important to underline that not only patients with the same biological characteristics achieved the same survival and the patients with the ECOG PS2 or patients that received [afatinib] in the second- or third-line have a shorter survival.

TARGETED ONCOLOGY:How encouraged are you by these interim efficacy findings?

Passaro:We find that the survival in clinical practice is very similar to the survival in randomized clinical trials. This is a good point for thoracic oncologists. We find that when we can use the drug before, the survival is better. If you use the EGFR TKI first-line or second-line, the survival is double compared to the third-line. This is very important.

The topic about the ECOG PS2 is the same for chemotherapy, targeted therapy, and immunotherapy. We know that the patients with ECOG PS2 have a shorter survival and we know that the patients with ECOG PS2 should be split for the cancer disease and comorbidities. In these findings, we found that the patients with ECOG PS2 have a shorter survival, but it is better than the data we have with chemotherapy in clinical practice.

The topic of uncommon mutations is very intriguing; we know that a patient with an uncommon mutation has a sensitive uncommon mutation and a resistant uncommon mutation. In our trial, about 80% of the uncommon mutations were exon 20 insertion. We know that these are resistant to EGFR TKIs, both first- and second-generation. In the future, we want to pool the data for an international pooled analysis of 2 phase IIIb trials. One study, this trial, is in the Caucasian population, and another in the Asian population. Maybe we can discuss these results by the end of the year.

TARGETED ONCOLOGY:Can you also discuss the findings for ALK TKIs in patients with metastatic NSCLC?

Passaro:We focus our attention on the clinical characteristics and treatment features of the patients that receive ALK inhibitors in clinical practice. We found that overall in about 21% of the patients treated with different ALK inhibitors, [these patients] achieved a 5-year survival. This is very amazing considering the pathology and the disease of lung cancer that typically has an OS benefit of [just] 1 year.

The findings we got from our research showed that the patient that received a palliative radiotherapy for oligoprogression for pain on bone have a more significant survival compared with those that did not receive the radiotherapy. The same findings were found when we evaluated the patients with high bulky disease, with stage 3 or 4 metastatic disease compared with the patients with a lower metastatic disease, stages 1 or 2. The survival is very, very significant in favor of the patients with a limited metastatic disease.

These findings are very interesting depending on the kind of drugs. In our analysis of data from patients treated in 2013, 90% of patients received crizotinib (Xalkori) in the first- or second-line setting, but these data are intriguing in the clinical practice.

TARGETED ONCOLOGY:What are the next steps with these data?

Passaro:It should be very interesting to compare the differentALKmutations and different alterations that drive the survival of the patients. Differing from theEGFRmutation, which is a different mutation with a different kind of molecular mechanism of resistance, in ALK disease we have a need to treat our patients based on the differentALKmutations. In the future, we need to understand if some of these disease driver mutations can help improve survival.

TARGETED ONCOLOGY:Are there any other ongoing trials you find particularly interesting?

Passaro:We have another poster at ELCC evaluating the role of immunotherapy in patients with aKRASmutation. We know that KRAS is a mutation without targeted agents and without active drugs directed to these mutations. In our analysis, we evaluated the role of immunotherapy in the first- and second-line setting for patients with aKRASmutation and evaluated the role of a co-mutation with theKRAS. The findings are preliminary, but interesting. It does not show a difference in a patient with or without aKRASmutation in the effectiveness of immunotherapy [treatment].