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mechanisms of resistance pathways become more diverse and

fragmented, then multiple treatment options may be required.
It has been reported that it may be possible to target some of
the additional EGFR inhibitor resistance mutations through
previous generations of inhibitors. For example, L718V could
be targeted by second-generation inhibitors such as afatinib or
dacomitib, although the level of efficacy which can be achieved
clinically (potentially due to modest wild-type margin) is not
fully understood.248 As discussed, if C797S is observed as a
resistance mechanism in the absence of T790M, early EGFR
inhibitors may be one current treatment option, but novel
agents could be considered as a treatment option for such
patients.247,250 For pathway-based resistance, where patients
show resistance to osimertinib due to cMET or RET
amplification, there are ongoing studies to combine with
small molecule cMET and RET inhibitors.251 Non-small-
molecule approaches are also being evaluated through this
rationale, such as the EGFR−cMET bispecific antibody (JNJ-
61186732) which is in phase II clinical trials, along with other
antibody-based approaches.252 In addition, additional path-
Figure 38. Modeled binding mode of osimertinib. Adapted with
ways are being targeted, one example being through the clinical
permission from ref 238. Copyright 2014 American Association for
Cancer Research. use of the HSP90 inhibitor luminespib.253
In terms of distinct chemical approaches there have been a
number of disclosures of compounds with some potential to
was subsequently approved in first-line therapy in 2018 based target these additional clinically relevant mutations. One
on a PFS of 18.9 months compared to the previous standard of emerging approach is to inhibit the clinically relevant
care of 10.2 months and was also the first to demonstrate an mutations with a reversible ATP pocket EGFR inhibitor,
improvement in overall survival (OS).239 Additional third- maintaining activity against T790M mutants but which does
generation T790M selective EGFR inhibitors have now been not require covalent binding toward C797. This has been
reported, some of which entered clinical trials including postulated to be as being particularly challenging based on the
olmutinib (Hanmi), PF-06747775 (Pfizer), EGF-816 (Novar- high ATP affinity of this mutant as described previously and
tis), naquotinib (Astellas), avitinib (ACEA), and lazertinib the reason why third-generation compounds utilized an
(Genesco/Yuhan/Janssen).240−244 irreversible covalent mechanism of action.254 However,
With third-generation inhibitors such as osimertinib Argenta/Genentech has disclosed reversible inhibitors with
providing a clear breakthrough in treatment options for reasonable cellular potency, although these did not enter
patients with EGFR-mutated NSCLC, the question of clinical development (Figure 39).255,256 The ALK inhibitor
additional resistance mechanisms has emerged. Initially brigatinib has also demonstrated preclinical activity against
speculated as a potential resistance mechanism to any covalent T790M mutant forms; however, clinical data on brigatinib as a
inhibitor of EGFR, the mutation of C797 to different amino single agent has not been compelling, although improved
acids (potentially serine which is relatively conservative) would preclinical efficacy was reported in combination with other
be expected to significantly reduce compound activity.107 With EGFR small molecule inhibitors and antibodies.257,258 More
cysteine being more nucleophilic than serine, the acrylamide recently, two agents called TQB3804 (Chia Tai Tianqing
group is unlikely to covalently bind to such a mutation, with Pharmaceutical Group Co., Ltd.)259 and BBT-176 (Bridge
the binding of ATP perhaps less impacted. The C797S Biotherapeutics, Inc.)260 have initiated phase I clinical testing
mutation has since been observed as a clinical resistance and have been reported to inhibit C797S mutant forms of
mechanism to third-generation EGFR inhibitors including EGFR.
osimertinib245 and olmutinib;246 however, the full under- Allosteric inhibitors of EGFR have also recently been
standing of the relative prevalence is still being established in reported; these however bind within the ATP pocket as
the first- and second-line disease indications. When the C797S opposed to the allosteric BCR/ABL inhibitors which bind in a
mutation emerges in the first-line osimertinib setting (i.e., separate pocket. The first allosteric inhibitor reported was
without T790M present), it has been shown to be sensitive to EAI045, which was shown to bind to the EGFR and ATP
first- and second-generation EGFR agents such as gefitinib; complex in the inactive c-helix out form to circumvent the
however, T790M may then emerge as an additional C797S resistant mutant, albeit with an “L858R-only” mutant
mechanism of resistance.247 Additional resistance mechanisms specific profile.118 These inhibitors are significantly less active
are also observed with rarer EGFR mutations such as L718V against the exon 19 deletion mutants where the c-helix out
and of L792,223,248,249 which have been suggested to have a form appears less accessible. In addition, minimal antiprolifer-
steric impact on the binding mode which slows down the ative activity was observed, although this was increased by
ability of the covalent bond to the inhibitor to form with combination with the EGFR antibody cetuximab. A recent
C797.110 Other mechanisms of resistance include cMET more potent analogue from this series (JBJ-04-125-02) has
amplification along with fusions such as RET. been reported which can bind alongside inhibitors such as
Drug discovery scientists have recently begun to hypothesize osimertinib to target emerging C797S resistant mutants
how such mutations could be targeted, leading to potential (Figure 40).118,261 As with BCR/ABL, the identification of
“fourth-generation” treatment options. However, as the allosteric inhibitors may enable not only the sequencing of
AD https://dx.doi.org/10.1021/acs.chemrev.0c00383
Chem. Rev. XXXX, XXX, XXX−XXX