EGFR exon 20 insertion (ex20ins) mutations are associated with primary resistance to currently approved EGFR TKIs with IC50 values for ex20ins 10-100 fold higher compared to the standard EGFR mutations (1). And, unlike other activating mutations, exon 20 insertions induce a conformational change with significant homology to the ATP-binding pocket of WT proteins. So, EGFR TKIs targeting ex20ins also need to improve selectivity for EGFRmut vs EGFRwt to limit treatment-related toxicities.
A small percentage of a large tumor type is still a lot of patients
In the US, 230K patients are diagnosed with NSCLC; even if ex20ins occurs in only 1%, that’s still 2,300 pts. The exact incidence of ex20ins mutations remains to be seen. Genomic analysis of large cohorts suggest between 3-5% of all EGFR mutations are ex20ins (2,3).
Unmet need
EGFR ex20ins does not respond to 2nd generation TKIs. The LUX-Lung subset analyses that led to the approval of afatinib in rare mutations (G719X, L861Q, S768I) showed little activity in the ex20ins cohort (9% ORR) (4). A phase 2 study dosing osimertinib at 80 mg/d concluded “Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5%”. A phase 2 study by ECOG-ACRIN dosed osimertinib at 160mg/d for an ORR of 24% (5,6).
Quick-to-market
Frontrunner mobocertinib expects to be on the market by mid-2021; early data from the pivotal ph 2 EXCLAIM study already earned Takeda a FDA BTD. No need to be an EGFR TKI to target the ex20ins space, though. Janssen recently announced FDA BTD for JNJ-61186372, their EGFR/MET bispecific antibody.
Mobocertinib (Takeda)
A 3rd generation TKI, designed to improve the therapeutic window for ex20ins mutations by reducing selectivity for EGFRwt.
In clinical development since 2016, early data from the phase 1/2 EXCLAIM study (NCT02716116) was first presented at ASCO 2019. At the recommended phase 2 dose (160mg/d), the response rate was 43% (12/28 pts) with a mPFS of 7.3 mo. Based on this data, FDA granted BTD in April 2020.
As for AEs, grade 3/4 diarrhea was high (18%), and 25% of pts required dose reductions. For comparison, the osimertinib phase 3 study in r/r NSCLC reported only 1% grade 3/4 diarrhea (7). Since early 2019, EXCLAIM added guidelines to proactively manage diarrhea.
Data from the pivotal extension cohort to be presented at ESMO (1261MO). Takeda plans to, or may have already, file an NDA and expects to be on the market 1H 2021. An ongoing confirmatory phase 3 (EXCLAIM-2, NCT04129502) compares mobocertinib to platinum-based chemotherapy in tx-naïve, EGFR ex20ins mutated NSCLC.
Poziotinib (Spectrum)
A 2nd generation TKI with a bit of history. Initially developed by Hanmi Pharma (Korea), poziotinib had been in clinical development since 2011. Licensed to Spectrum in 2015 based on available phase 1 data that showed responses in 6/10 HER2pos MBC pts (8). Subsequent studies in HER2pos tumors, including combinations with HER2-targeted therapy, were hampered by lower than expected efficacy and toxicity issues (diarrhea, rash).
Spectrum switched its focus when preclinical research by MD Anderson identified poziotinib as especially active against ex20ins mutated EGFR (9). A subsequent MDACC-sponsored phase 2 study in ex20ins NSCLC showed responses in 7 out of the first 11 pts (64%) enrolled (NCT03066206)
The multi-cohort, Spectrum-sponsored ZENITH20 study was initiated in 2017 (NCT03318939). Cohort 1 enrolled 115 pts with EGFR ex20ins mutated, r/r NSCLC; ORR by BIRC was 15%, with a mPFS of 4.2 mo (AACR 2020). Spectrum announced that the minimum threshold of response was not met; however, cohort 3 (EGFR ex20ins tx-naïve NSCLC) did meet the threshold and data is expected at ESMO (LBA60).
Tarloxotinib (Rain Therapeutics)
Developed by the U. of Auckland (NZ), tarloxotinib is a hypoxia activated prodrug of the panHER TKI tarloxotinib-E. This class of agents depend on enzymatic reduction under hypoxic conditions to release high levels of active drug within the tumor, while limiting systemic exposure.
Tarloxotinib was initially licensed to Threshold for clinical development. But in 2016, Threshold Pharma announced that a ph2 proof-of-concept study in EGFRmut, r/r NSCLC did not meet efficacy requirements (no responses) and the program was discontinued.
Meanwhile, ex20ins mutations were shown to be resistant to standard TKIs due to much higher IC50 values (1). Sufficient inhibition would require dose levels that are clinically unachievable due to toxicities. Since tarloxotinib was designed to increase the dose-intensity of active drug within the tumor, it could potentially overcome these limitations. Research by U. of Auckland provided preclinical proof-of-principle in ex20ins in xenografts (10).
Rain, formed in 2017, in-licensed the abandoned drug for further clinical development. A study initiated in 2019 is enrolling cohorts with specific mutations only, including ex20ins mutated NSCLC (NCT03805841). First clinical data from this study is expected at ESMO (LBA61).
CLN-081/TAS6417 (Cullinan Pearl)
A newcomer with a First-in-Human study initiated in 2019 (NCT04036682). Discovered by Taiho, CLN-081 was licensed for ex-Japan development in early 2019 to newly formed, US-based Cullinan Pearl. Like mobocertinib, CLN-081 is 3rd generation TKI, designed to improve the therapeutic window for ex20ins mutations by reducing selectivity for EGFRwt (11).
Reference
1. Hirano et al., Oncotarget 2015 (PMID: 26515464)
2. Harrison et al., Sem in Cancer Biol. 2020 (PMID: 31562956)
3. Mack et al., Cancer 2020 (PMID: 32365229)
4. Yang et al., Lancet Oncol. 2015 (PMID: 26051236)
5. Piotrowska et al., ASCO 2020: 9513
6. van Veggel et al., Lung Ca. 2020 (PMID: 31926441)
7. Mok et al., NEJM. 2017 (PMID: 27959700)
8. Kim et al., Cancer Res Treat. 2018 (PMID: 28859471)
9. Robichaux et al., Nat Med. 2018 (PMID: 29686424)
10. Estrada-Bernal et al., AACR-EORTC-NCI 2017: A157
11. Udagawa et al., Mol Cancer Res. 2019 (PMID: 31467113)
