Precision targeted therapy to treat lung cancer mutations: 91% of patients have tumors shrunk!

Precision targeted therapy to treat lung cancer mutations.  There are many types of lung cancer, and there is the possibility of cancer mutation. Therefore, the treatment is very difficult.

Recently, the US FDA granted Poziotinib a fast track designation for use in previously treated non-small cell lung cancer patients with EGFR/HER2 exon 20 mutations. It is expected to submit a new drug application (NDA) later this year.

Currently, there is no approved treatment for lung cancer with rare EGFR/HER2 exon 20 insertion mutations.

▌Refractory lung cancer mutations that cannot be ignored

Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer, accounting for about 85% of all lung cancers.

The most common driver mutation of NSCLC is EGFR gene mutation, which is present in about 15%-20% of NSCLC patients and about 50% of Asian lung cancer patients.

Currently, common EGFR mutation inhibitors (EGFR TKIs) include: first-generation gefitinib, erlotinib, and icotinib; second-generation afatinib and dacomitinib; third-generation osimertinib and so on.

These drugs have greatly prolonged the progression-free survival and overall survival of most patients with EGFR mutations, but patients with lung cancer with exon 20 mutations have little effect.

There are dozens of subtypes of EGFR mutations, of which over 80% of the mutations are in exons 19 and 21, and they are also sensitive to EGFR TKI inhibitors, with good targeted therapy effects. The insertion mutation in exon 20 accounts for only 10%, which is a refractory mutation and is not sensitive to TKI treatments that have been approved for marketing, and the prognosis is poor.

Among all NSCLC patients, the proportion of patients with EGFR/HER2 exon 20 mutations is not high, only 4%. However, due to the high incidence and mortality of lung cancer in China, it cannot be ignored.

Currently, the standard regimen for such patients is chemotherapy or combined immunotherapy. There is no approved targeted therapy yet, and new treatment options are urgently needed.

▌Broad spectrum HER inhibitor: Poziotinib

Poziotinib is an innovative broad-spectrum HER inhibitor that can irreversibly block the signal transmission of HER family tyrosine kinase receptors (including HER1, HER2 and HER4), thereby inhibiting tumor cell proliferation.

For the HER receptor with EGFR exon 20 insertion mutation, preclinical trials have shown that the inhibitory effect of Poziotinib on them is dozens of times that of existing tyrosine kinase inhibitors.

Currently, the drug is undergoing a number of clinical trials, including breast cancer, lung cancer, stomach cancer, head and neck cancer, etc.

In 2019, Poziotinib was approved for clinical trials in China, and its indications are: treatment of NSCLC patients whose tumors express epidermal growth factor receptor (EGFR, HER1 or ERBB1) or HER exon 20 insertion mutations.

▌91% of tumors have shrunk, innovative drugs show miraculous effects!

This determination is based on positive data from cohort 2 of the Phase 2 ZENITH20 clinical trial. ZENITH20 is a multi-center, multi-cohort Phase 2 clinical trial designed to evaluate the efficacy and safety of Poziotinib in NSCLC patients with EGFR exon 20 insertion mutations.

The results published at the ESMO TAT virtual conference in 2021 showed that Poziotinib (16mg) produced clinically significant activity in newly treated NSCLC patients with EGFR exon 20 mutations.

The results show that:

The objective response rate in the Poziotinib treatment group was 27.8%, and the disease control rate (DCR) was 86.1%.

After a median follow-up of 9.2 months, 12 of the 79 patients continued to receive Poziotinib, and the median duration of response (DOR) for this population was 6.5 months.

It is worth noting that in the intention-to-treat (ITT) population, 91% of patients after Poziotinib treatment showed tumor shrinkage.

In addition, the preliminary results of the trial cohort 5 showed that in patients with metastatic non-small cell lung cancer with mutations in EGFR or HER2 exon 20, the toxicity of the patients was reduced by twice daily administration.

• In cohort 1, the results announced at the 2020 American Association for Cancer Research (AACR) annual meeting showed:

The ORR of Poziotinib was 14.8%, the disease control rate was 68.7%, the median progression-free survival was 4.2 months, and the median DOR was 7.4 months. Although this cohort did not meet the primary endpoint of ORR, Poziotinib reduced tumors in 65% of patients.

The data of cohort 3 and cohort 5 were announced at the ESMO Targeted Anticancer Therapy Conference 2021, showing:

• In cohort 3, among the newly treated patients, the ORR of the Poziotinib treatment group was 27.8%, the DCR was 86%, the median PFS was 7.2 months, and the median DOR was 9.2 months.
• In cohort 5, low-dose administration twice a day, Poziotinib has a low incidence of serious adverse reactions (AEs), which is expected to further improve the tolerability and safety of the drug.

For this rare target, in addition to Poziotinib, there are innovative drugs such as Amivantamab, TAK-788, and JNJ-372 double antibodies for the treatment of NSCLC patients with EGFR exon 20 insertion mutations. Among them, Amivantamab submitted a biologics license application to the FDA at the end of last year, hoping that these innovative drugs can benefit more patients.

(source:internet, reference only)

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