Frontline Afatinib Shows Promise in EGFR+ NSCLC

Antonio Passaro, MD, PhD

Afatinib (Gilotrif) was found to have clinical activity and be well tolerated in patients with EGFR mutation—positive non–small cell lung cancer (NSCLC), which is consistent with data from the LUX-Lung (LL) 3/6 trials comparing frontline afatinib to standard chemotherapy in a similar patient population, according to results from a phase IIIb interim analysis.

In the LL 3/6 trials, patients with EGFR-mutant NSCLC were treated with first-line afatinib compared with chemotherapy, which led to a significantly improved progression-free survival (PFS). In LL 3/6, results showed that the median PFS in patients who received the EGFR TKI was 11.1 months compared with 6.9 months in those who received chemotherapy.

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 performance status of 2 or an uncommon mutation had a median PFS of 6.2 and 6.0 months, respectively. Exon 20 mutations accounted for 80% of the uncommon mutations, which are known to be resistant to EGFR TKIs.

Patients with locally advanced or metastatic EGFR-positive NSCLC with an ECOG performance status of 0 to 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.

In an interview with OncLive, 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 with EGFR mutation-positive NSCLC and discussed results from other studies investigating ALK and KRAS mutations in patients with NSCLC.

OncLive: Could you discuss the interim findings from the phase IIIb trial of afatinib in patients with EGFR-mutant 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 for EGFR-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.

How encouraged are you by these interim efficacy data?

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.

What about findings with ALK TKIs in patients with metastatic NSCLC?

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 III or IV 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.

What are the next steps with these data?

It should be very interesting to compare the different ALK mutations and different alterations that drive the survival of the patients. Differing from the EGFR mutation, 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 different ALK mutations. In the future, we need to understand if some of these disease driver mutations can help improve survival.

Are there any other ongoing trials you find particularly interesting?

We have another poster at ELCC evaluating the role of immunotherapy in patients with a KRAS mutation. 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 a KRAS mutation and evaluated the role of a co-mutation with the KRAS. The findings are preliminary, but interesting. It does not show a difference in a patient with or without a KRAS mutation in the effectiveness of immunotherapy [treatment].

References

1. Passaro A, Laktionov KK, Poltoratskiy A, et al. Afatinib in EGFR TKI-naïve patients with locally advanced metastatic NSCLC harboring EGFR mutations: an interim analysis of a phase IIIB trial. Ann Oncol. 2019;30 (2):ii38-ii68. doi: 10.1093/annonc/mdz063.
2. Yang JC-H, Schuler MH, Yamamoto N, et al. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol. 2017;30(18). doi: 10.1200/jco.2012.30.18_suppl.lba7500.