Overcoming resistance to anti-EGFR therapy — where do we stand?

Abstract

In the past few years, the mechanisms leading to an acquired resistance to anti-EGFR monoclonal antibodies became an important topic in metastatic colorectal cancer research. In this commentary, we briefly summarize the latest update to this field by Arena and colleagues, and discuss promising new drugs and treatment strategies that might lead to overcoming secondary resistance.

The epidermal growth factor receptor (EGFR) signalling pathway is crucial to colorectal cancer (CRC) initiation and progression. The monoclonal antibodies cetuximab and panitumumab inhibit EGFR by targeting its extracellular domain (ECD), and have clinically meaningful activity in terms of disease remission and survival in metastatic CRC (mCRC)¹. Patients with oncogenic mutations in the RAS gene family (in particular KRAS and NRAS) derive no benefit from anti-EGFR therapy due to primary resistance. Mutations in other genes implicated in downstream signalling, such as BRAF and PIK3CA, have also been proposed as additional mechanisms of primary resistance, but their clinical relevance is still marginal. In the past 3 years, research has focused on mechanisms of secondary resistance, which leads to disease progression after an initial therapeutic response. Now, in a new report from Arena et al., MM-151, an oligoclonal anti-EGFR antibody, has demonstrated efficacy in patients with acquired resistance to cetuximab or panitumumab due to secondary mutations within the EGFR ECD².

Mechanisms leading to acquired resistance are complex but can frequently involve: target modifications, such as the development of mutations within the EGFR ECD (resulting in the the amino acid changes Ser492Arg, Arg451Cys, Ser464Leu, Gly465Arg, Lys467Thr, or Ile491Met; 15% of cases); the emergence of mutations in RAS, BRAF or other downstream effectors, in particular PIK3CA (40% of cases); or the activation of collateral pathways that overcome EGFR inhibition, such as ERBB2 (also known as HER2) or MET (15% of cases). Remarkably, although the genetic drivers of primary resistance are usually homogeneous within an individual tumour, more than one molecular mechanism of secondary resistance can emerge in a single tumour at progression³. Resistant clonal populations not detectable at baseline can thrive under treatment pressure and lead to acquired resistance. Importantly, mechanisms of secondary resistance might be detected through so-called liquid biopsies, which are sensitive assays that detect relevant mutations in circulating cell-free DNA or RNA in the blood or urine. These novel technologies enable monitoring of dynamic actionable alterations or tumour hetero geneity, and can identify molecular escape mechanisms before disease progression is clinically documented. For example, in patients with wild-type RAS receiving cetuximab or panitumumab, liquid biopsies enable the identification of new mutations from blood samples when acquired resistance to anti-EGFRs occurs prior to clinical or radiographical disease progression⁴.

A mechanism of escape from anti-EGFR sensitivity is the appearance of ECD EGFR mutations. MM-151 inhibits EGFR by binding multiple regions of its ECD, consequently blocking downstream pathways and enhancing the innate antitumour immune response in preclinical and patient-derived xenograft models⁵. Arena et al. have shown that in the presence of ECD mutations, EGF can still bind its receptor and promote effective EGFR activation. Furthermore, MM-151, but not cetuximab or panitumumab, could inhibit ECD-mutant EGFR and its associated pathways. These preclinical findings were confirmed in two patients who developed ECD EGFR mutations after cetuximab and panitumumab therapy, but subsequently responded to MM-151. Interestingly, tumour shrinkage was associated with decreased circulating cell-free DNA levels of mutant EGFR². Thus, these data provide strong rationale for prospective clinical trials evaluating MM-151 in patients who develop ECD EGFR mutations after treatment with cetuximab or panitumumab.

A recent report from the same group showed similar findings with Sym004, a mixture of two non-overlapping anti-EGFR antibodies. In preclinical and xenograft models, Sym004 was able to effectively bind mutant EGFR and suppress downstream signalling⁶, showing promising activity in a phase I and an ongoing phase II trial (ClinicalTrials.gov NCT01117428 and NCT02083653) of patients with mCRC who acquired anti-EGFR resistance. MM-151 and Sym004 share mechanisms of action and have shown encouraging clinical activity thus far, suggesting that they might both become treatment options in patients with mCRC whose tumours have ECD EGFR mutations. If these intriguing data are validated, the adoption of next-generation anti-EGFR therapies might represent the next paradigm in the treatment of patients with mCRC and wild-type RAS. However, many questions remain regarding the integration of these agents into earlier lines of therapy (including in panitumumab or cetuximab-naive patients), the optimal combination with chemotherapeutic agents, long-term toxicity profiles and the comparative efficacy of MM-151 versus Sym004.

The understanding of secondary resistance mechanisms, and the identification of innovative technologies, such as liquid biopsies, will lead to the development of novel drugs and treatment strategies based on the type of molecular escape (TABLE 1). Preliminary results from the HERACLES trial provide such an example. In this study, chemo-refractory patients with wild-type KRAS and ERBB2 amplification received trastuzumab with lapatinib (agents that target the extracellular and kinase domains of erbB-2, respectively), achieving a 35% response rate and 34% disease stabilization⁷.

Table 1 |.

Ongoing trials for mCRC and secondary resistance to anti-EGFR therapy

Mechanism of secondary resistance	Drugs under investigation	ClinicalTrials.gov reference	Phase
RAS mutations	Panitumumab + MEK inhibitor (MEK162)	NCT01927341	II
MET amplification	Cetuximab + MET inhibitor (INC280)	NCT02205398	II
MET overexpression	Cetuximab + MET inhibitor (tivantinib)	NCT01892527	II
BRAF mutation	MEK inhibitor (trametinib; GSK1120212) + BRAF inhibitor (dabrafenib; GSK2118436) + panitumumab	NCT01750918	I/II

EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer.

Still controversial is the role of re-challenge after progression on cetuximab or panitumumab. Retrospective and prospective series have yielded conflicting results in terms of the clinical benefit derived from anti-EGFR re-challenge therapy, though selection bias and incomplete RAS evaluation might confound the interpretation of these studies⁸. The effect of retreatment with cetuximab and irinotecan-based therapy was evaluated in patients with mCRC and the wild-type KRAS gene, who had an initial response to cetuximab and irinotecan but received a different line of therapy after progression. Promising results in terms of response rate (53.8%) were observed, suggesting that patients who derive benefit from initial anti-EGFR treatment, then have a long anti-EGFR-free interval, are more likely to benefit from a re-challenge⁹. On the basis of these observations, the phase II CRICKET trial is ongoing. In this study (ClinicalTrials.gov NCT02296203), patients with irinotecan- resistant mCRC and wild-type KRAS, NRAS or BRAF, who progress after an initial response to a first-line cetuximab therapy, receive a re-challenge as a third-line treatment with cetuximab plus irinotecan. Molecular monitori ng through liquid biopsies will be critical in addressing whether anti-EGFR therapy re-challenge is a reasonable option, as such observations are corroborated with a strong biological explanation. In circulating cell-free DNA analyses, 60–80% of KRAS wild-type patients receiving anti-EGFR monoclonal antibodies develop KRAS or NRAS mutations during treatment. Interestingly, 50% of patients have no detectable circulating RAS mutation upon anti-EGFR drug withdrawal, leading to renewed drug s ensitivity¹⁰.

In conclusion, thanks to a more refined understanding of the mechanisms leading to anti-EGFR therapy secondary resistance, in addition to the increasing adoption of liquid biopsies into clinical practice, treatment strategies for wild-type RAS mCRC stand to be revolutionized in the near future. However, many validation steps are still required, such as the standardization of circulating cell-free DNA mutation detection techniques, as well as a deeper knowledge of next-generation anti-EGFR therapeutics.