麻豆果冻传媒影音

Adding a vaccine against epidermal growth factor (EGF) to an EGFR inhibitor led to a high response rate and durable activity in advanced EGFR-mutated non-small cell lung cancer (NSCLC), a small pilot study showed.

The treatment led to objective responses in 18 of 23 patients, and all but one patient derived clinical benefit. Median progression-free survival (PFS) approached 1.5 years, and median overall survival (OS) had yet to be reached.

Serum antibody assessment revealed sustained increases in EGF antibodies, indicative of immunogenic activity, reported Silvia Garcia-Roman, PhD, of Dexeus University Hospital in Barcelona, at the virtual World Conference on Lung Cancer (WCLC).

"Results of the demonstrate that an anti-EGF vaccine combined with afatinib (Gilotrif) is well tolerated and induces a sustained immunogenic effect," she concluded. "Vaccination against EGF might enhance the efficacy of EGFR tyrosine kinase inhibitors (TKIs) and delay the emergence of resistance."

The trial reflected ongoing efforts to enhance the efficacy and durability of standard-of-care treatment for EGFR-mutated NSCLC. Patients with advanced NSCLC associated with EGFR mutations often respond to EGFR inhibitors but ultimately relapse following development of resistance mutations.

In , the anti-EGF vaccine inhibited EGF-induced cell proliferation and downstream signaling in EGFR-mutated cells. Sera from patients treated with the vaccine inhibited activation of EGFR effector cells, enhanced the activity of TKIs evaluated, and delayed the emergence of resistance clones. More recently, Garcia-Roman and colleagues reported in NSCLC cells with ALK and RET rearrangement.

The preclinical evidence provided the basis for a phase I clinical trial to evaluate the safety and immunogenicity of the vaccine in combination with afatinib in untreated advanced EGFR-mutated NSCLC. The trial had an accrual target of 30 patients but enrollment stopped early because of the COVID-19 pandemic. The common EGFR aberrations of exon 19 deletion and L858R mutation in exon 21 account for 19 of the 23 cases of NSCLC.

Treatment began with a 3-day run-in with cyclophosphamide and afatinib, followed by daily afatinib until disease progression. Patients received the anti-EGF vaccine every 2 weeks from day 1 to day 43, then on day 92, and then every 2 months until disease progression.

Garcia-Roman did not show specific data relative to the treatment's safety but said adverse events (AEs) were consistent with single-agent afatinib, "suggesting the vaccine did not increase the risk of adverse events." Grade 3/4 AEs occurred in 11 patients, and three grade 5 (fatal) events occurred.

Efficacy data showed an overall response rate of 78% and disease control rate of 96%. Tumor reduction from baseline averaged 57%. After a median follow-up of 11 months, the median PFS was 17.4 months. More than 90% of responses were ongoing at 11 months, said Garcia-Roman.

Anti-EGF antibodies increased significantly from baseline to 3 months and remained stable thereafter. Circulating levels of EGF decreased rapidly from baseline to 3 months and remained significantly (P<0.0001) lower to the end of the study. Levels of tumor growth factor-alpha also decreased but not significantly. Laboratory studies of posttreatment patient sera exhibited sustained evidence of anti-EGF activity.

The small number of patients in the trial limits the conclusions that can be drawn from the results, said WCLC invited discussant Giannis Mountzios, MD, PhD, of Henry Dunant Hospital Center in Athens. Another limitation is the relative homogeneity of the activating mutations represented in the study population.

The median PFS of 17.4 months compared favorably with the 13.6-month median PFS in the subgroup of patients with common mutations in the randomized , which compared afatinib versus chemotherapy, Mountzios continued. The data suggest the possibility of synergism between the vaccine and apatinib, but he acknowledged the need for cautious interpretation of such cross-trial comparisons involving small patient numbers.

Mountzios questioned Garcia-Roman's observation that the vaccine had no additive effect on toxicity.

"I would like to know more about the structure and the properties of the anti-EGF vaccine, and I would like to have more information on the additive toxicity, especially in terms of frequent adverse events that we see with anti-EGF and anti-EGFR agents," he said. "I am personally concerned about the three grade 5 events among 23 participants, and I would like to have more data on the circumstances of these grade 5 events."

Mountzios also suggested that evaluation of the vaccine with newer anti-EGFR agents, especially osimertinib (Tagrisso), "would be really interesting to see if these novel combinations could further enhance efficacy."

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