Research Highlights
Gini Harrison, our Research Trustee, has done a round-up of research activity. Even in the quieter holiday months science continues to bring us new innovations and hope.
Potential new treatment for EGFR+ LC with L858R mutation
We know that treatment with TKIs can be very effective, but these medications tend to lose effectiveness over time, as tumours develop secondary mutations that enable them to resist therapy. So, research is underway to identify alternative treatment avenues that patients do not develop resistance to. One such study1, published in the journal “Cell Reports Medicine”, has identified a potential new treatment for EGFR patients with the L858R mutation. In this case, researchers have found that using an antibody drug called cetuximab (also known as Erbitux), may be effective for treating patients with the L858R mutation (which affects approximately 40% of those with EGFR positive lung cancer). This research is still in its infancy, but using a mouse model, researchers at the Weizmann Institute were able to effectively shrink L858R mutated lung tumours in mice, without any sign of resistance or relapse using this antibody drug. They found that the drug is effective for L858R mutations, because this specific mutation causes receptors to pair up in the cancer cell membrane, signalling cellular replication and tumour growth. However, cetuximab blocks this receptor pairing. If successful, These findings suggest that this might be a viable treatment option for lung cancer patients with the L858R mutation in the future, so the researchers are now preparing for a clinical trial to validate the treatment’s effectiveness in humans.
Combining Osimertinib with chemotherapy
Results from the FLAURA2 Phase III trial2 showed that giving Tagrisso (osimertinib) in combination with chemotherapy leads to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to Tagrisso alone (or “monotherapy”) in patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFR lung cancer. As a result of these findings, this month has seen the US grant this drug combination a Breakthrough Therapy Designation for EGFR positive lung cancer. This designation is important, as it means the development and review of this treatment regime can be fast-tracked… meaning that they are likely to get to us (the patients) faster. While treatment availability in the US and UK can be quite different, decisions to make treatments available on the NHS are based on evidence worldwide. So, this means we may be seeing this treatment combination being offered in the UK relatively soon.
Reversing resistance to Osimertinib, new trial gives hope
In a new study in the journal Cancer Cell3, researchers at the Dana-Farber Cancer Institute and Yale Cancer Center have potentially found a way to reverse resistance to osimertinib in a subset of EGFR-mutant lung tumors. In their ongoing Phase 1 trial, the researchers are investigating whether a specific class of drugs (known as SWI/SNF disruptors) offer a way to restore the potency of osimertinib in these tumours. This research is in its very early stages, but initial results suggest this might be one to watch!
Promising new drug for EGFR+ Exon 20 mutation
A new drug regime is also looking promising for patients with EGFR exon 20 mutations. Since our last newsletter, the results from a phase 1/2a trial of zipalertinib (also known as CLN-081 and TAS6417) were published in the Journal of Clinical Oncology4. The findings showed more than half of the participants achieved stable disease with the drug, and 38.4% had a partial response. Average time before progression was 10 months. Compared to other Exon 20 drugs (such as amivantamab and mobocertinib), the side-effects were very tolerable, with no patients reporting really bad (grade 3 or more) adverse effects. Building on these results, Taiho Pharmaceutical and Cullinan Oncology have now launched a Phase III trial of zipalertinib as a first-line treatment for patients with advanced Exon 20 patients. This trial is known as REZILIENT3 and will investigate the efficacy and safety of Zipalertinib plus platinum-based chemotherapy in this patient group.
Lazertinib in first line setting looks positive
Findings from the global, phase 3 LASER301 trial5 demonstrated that lazertinib, a potent, third-generation TKI, had significantly improved efficacy compared to gefitinib in a first-line setting among patients with EGFR-mutated locally advanced or metastatic NSCLC. In the LASER301 study, 393 patients were randomized to receive either 240 mg lazertinib or 250 mg gefitinib. The average duration or response in the lazertinib arm was 19.4 months, compared to 8.3 months in the gefitinib arm. It is still too early to judge the impact on overall survival rates, but initial results look positive.
Research into the quality of life of EGFR + lung cancer patients
The Ruth Strauss Foundation has just launched their first ever research grants programme for non-smoking related lung cancers6. Their grants programme will award funding of up to £50,000 to promising research/projects that focus on improving the lives of people with non-smoking lung cancers. This might be by: increasing public understanding and awareness of non-smoking lung cancers; enhancing understanding of who is diagnosed with non-smoking lung cancer; improving the process or experience of being diagnosed or being treated; improving how the psychological, information, financial and practical needs of people with non-smoking lung cancer are met during and beyond active treatment. So if you know anyone who might be interested in applying for the grant, please do let them know. And please share far and wide. There is very little research in the quality of life of EGFR patients… hopefully this grant will help to change that!
Gini Harrison, Research Trustee
References
Marrocco et al. (2023). L858R emerges as a potential biomarker predicting response of lung cancer models to anti-EGFR antibodies: Comparison of osimertinib vs. cetuximab. Cell Reports Medicine 4, 101142 (https://www.cell.com/cell-reports-medicine/pdfExtended/S2666-3791(23)00295-1)
Astrazenica (2023) https://www.astrazeneca.com/media-centre/press-releases/2023/tagrisso-plus-chemo-improved-pfs-in-lung-cancer.html
de Miguel, F. J., Gentile, C., Feng, W. W., Silva, S. J., Sankar, A., Exposito, F., ... & Politi, K. A. (2023). Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer. Cancer Cell.
Piotrowska Z, Tan DSW, Smit EF, et al. Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor exon 20 insertions. J Clin Oncol. Published online June 29, 2023. doi:10.1200/JCO.23.00152
Cho B, Ahn MJ, Kang JH, et al. Lazertinib versus gefitinib as first-line treatment in patients with EGFR-mutated advanced non–small-cell lung cancer: Results from LASER301. J Clin Oncol. Published online June 28, 2023. doi:10.1200/JCO.23.00515
https://ruthstraussfoundation.com/grants-programme/