How does the treatment of non-small cell lung cancer overcome EGFR and ALK inhibitor resistance?

Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are drivers of non-small cell lung cancer (NSCLC), and their discovery and development of targeted therapies advance biomarker-based precision treatment models for advanced patients developme.

Recently, Nature Reviews Clinical Oncology, a sub-journal of "Nature", published a review entitled "Third-generation EGFR and ALK inhibitors: resistance mechanisms and management", detailing the resistance to third-generation EGFR and ALK inhibito.

Introduction to osimertinib and lorlatinib

Osimertinib is a third-generation, irreversible EGFR TKI with greater potency and selectivity for typical EGFR activating mutations and T790M resistance mutatio.

However, despite the remarkable efficacy of third-generation EGFR and ALK TKIs, acquired resistance is inevitable and remains an unsolved probl.

Mechanisms of resistance to osimertinib and lorlatinib

Broadly speaking, acquired resistance can be classified as on-target resistance (involving changes in target kinases such that persistent kinase activation and signaling occurs even in the presence of a TKI) or off-target resistance Off-target resistance (involving upregulation of downstream signaling proteins at the target or activation of one or more alternative signaling pathways following cellular phenotype transformatio.

target-dependent resistance mechanisms

In terms of target-dependent resistance to osimertinib, osimertinib binds to EGFR by forming a covalent bond with cysteine ​​797 (C797) located at the ATP-binding si.

Most of the target-dependent drug resistance mutations for lorlatinib are compound ALK gene mutatio.

Target-independent mechanisms of drug resistance

Historically, the study of non-target-dependent resistance mechanisms has been more challenging because these mechanisms may involve non-genome or non-cell-autonomous mechanisms that may not be identified using tumor sequenci.

MET amplification is the first resistance mechanism involving alternative signaling identified in EGFR-mutant NSC.

In addition, downstream signaling pathways of EGFR and/or ALK can be reactivated and mediate drug resistan.

▲Mechanisms of acquired resistance to osimertinib and lorlatinib in EGFR-mutated and ALK-rearranged NSCLC: including mutations that prevent TKI from inhibiting target receptor tyrosine kinases (a), bypass and/or downstream signaling Pathway activation (b), and changes in tumor cell lineages such as transformation from adenocarcinoma (ADC) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC) phenotype and epithelial-mesenchymal transition (EMT) (c) ( Image source: Reference [1])

The transformation of histological features of cancer is also one of the important mechanisms of drug resistan.

Multiple strategies to overcome drug resistance

The rate and pattern of clinical disease progression varies widely among patients following targeted therapy, including osimertinib and lorlatin.

For example, local excision or stereotactic radiation therapy may be used in patients who have had small metastases in only one or a few places in the body after treatme.

Next-generation EGFR and ALK inhibitors

For patients with progressive diffuse, systemic disease, a change in the approach to systemic therapy is necessa.

Many fourth-generation EGFR and ALK TKIs are currently in development to address target-dependent resistance to third-generation TK.

▲Activity characteristics of BLU-945 and BLU-701 (Image source: Blueprint Medicines official website)

At the recently concluded AACR conference, Blueprint Medicines announced preliminary proof-of-concept clinical data for BLU-94 Early clinical trial data showed that BLU-945 demonstrated a favorable safety profile and a dose-dependent reduction in circulating tumor D.

▲BLU-945 dose-dependently reduces circulating tumor DNA (Image source: Blueprint Medicines official website)

Other fourth-generation EGFR inhibitors include EAI045 and JBJ-04-125-02, both of which are allosteric EGFR inhibito.

In the development of novel ALK TKIs, TPX-0131 developed by Turning Point Therapeutics is a fourth-generation ALK TKI with a compact macrocyclic structure that can fully bind to the adenine site in the ATP pocket, even in the presence of ALK resistance mutations ALK can also be inhibited in the presenceof The compound is currently in Phase 1 clinical tria.

In addition, NVL-655, a next-generation CNS-penetrating ALK inhibitor developed by Nuvalent, is expected to enter Phase 1 clinical trials in 202 It is worth mentioning that a single innovative ALK TKI may not be sufficient to overcome all compound mutations that lead to lorlatinib resistan.

This also highlights the difficulty of effectively inhibiting the target once the tumor has accumulated compound mutatio.

combination therapy

Combination therapy may resolve or delay the onset of resistance to third-generation inhibitors by combining third-generation EGFR or ALK inhibitors with other dru.

First, early and third-generation TKIs targeting the same target can be used concurrently to address or delay the emergence of target-dependent resistan.

For example, in EGFR-mutant NSCLC, the combination of osimertinib with a first-generation EGFR TKI can overcome resistance associated with the C797S mutation in certain allelic backgroun.

Another strategy for combination therapy is the use of EGFR or ALK TKIs with another targeted therapy to target non-target-dependent resistan.

For example, in patients with ALK-rearranged NSCLC, combinations of lorlatinib with MET inhibitors (targeting MET to drive resistance), MEK inhibitors (targeting RAS-MAPK signaling reactivation), or SHP2 inhibitors The treatments are all being evaluated in clinical tria.

Researchers are also now exploring the effects of combining EGFR or ALK TKIs with antiangiogenic drugs or immunothera.

However, the results of current clinical trials cannot determine whether the combination therapy can bring about a significant improvement in effica.

Innovative therapies and future directions

The article points out that antibody-drug conjugates (ADCs) and bispecific antibodies are new types of treatments currently being develop.

They may be effective in patients with TKI-resistant cance.

These drugs have the potential to overcome multiple resistance mechanisms and therefore deserve special attenti.

For example, amivantamab, a bispecific antibody targeting EGFR and MET, has received accelerated FDA approval for the treatment of NSCLC patients with EGFR exon 20 insertion mutatio.

Moreover, it was combined with the third-generation EGFR inhibitor lazertinib to achieve an objective response rate (ORR) of 36% and a median progression-free survival of 9 months in osimertinib-treated patients with specific mutatio.

Notably, even in the subgroup of patients without EGFR- or MET-based biomarkers, an ORR of 29% was still observ.

This supports the possible broad application of this strate.

Another example is the HER3-targeting antibody-drug conjugate patritumab deruxtec.

HER3 expression is often elevated in resistant tumors harboring EGFR mutations, and inhibition of EGFR activity improved the anticancer activity of patritumab deruxtecan in preclinical mode.

Patritumab deruxtecan has been granted breakthrough therapy designation by the.


FDA as a single agent for the treatment of patients with drug-resistant EGFR mutations who have progressed during or after treatment with third-generation tyrosine kinase inhibitors and platinum-based thera.

Patients with metastatic or locally advanced NSC.

These evidence support the exploration of patritumab deruxtecan in combination with third-generation EGFR inhibito.

Other innovative therapeutic strategies, including cancer vaccines, are also expected to treat patients with EGFR- and ALK-driven NSC.

A DNA-based ALK vaccine has elicited robust immune responses in mouse models of ALK-driven lymphoma and NSCLC, laying the groundwork for exploring anti-ALK vaccines as an innovative therapeutic strate.

Individualized neoantigen vaccines, as single agents, or in combination with EGFR inhibitors, are also now being tested in early-stage clinical tria.

The authors note that the discovery of activating EGFR mutations and ALK rearrangements brings a paradigm shift in the treatment of NSC.

However, drug resistance remains an unresolved challen.

Current collaborations in basic, translational and clinical research will provide a deeper and broader mechanistic understanding of the biology of TKI-resistant cancers, enabling the rational development of innovative therapeuti.

References

[1] Cooper et .

, (2022), Third-generation EGFR and ALK inhibitors: mechanisms of resistance and manageme.

Nat Rev Clin Oncol, https://d.

org/11038/s41571-022-00639-9