Back from the brink: EGFR inhibition in gastroesophageal cancer

Summary

Gastroesophageal adenocarcinomas (GEA) remain difficult to treat with limited targeted therapeutics. Negative results from randomized trials of Epidermal Growth Factor Receptor inhibitors (EGFRi) in molecularly unselected GEA patients have hampered the development of EGFRi in the gastroesophageal cancer space. A recent study reopens the game.

In this issue of Clinical Cancer Research, Corso and colleagues (1), present new evidence supporting the rationale to target the Epidermal Growth Factor Receptor (EGFR) pathway in molecularly-defined gastroesophageal adenocarcinomas (GEA). Through molecular profiling of four GEA cohorts, they show that EGFR amplification is present in a small but significant proportion of patients (≈7%), and correlates with adverse biology and poor outcome. Using patient derived xenografts (PDXs) the authors identify dual EGFR inhibition as a novel strategy to target EGFR amplified tumors and define new mechanisms of primary resistance (1).

Despite some advances in the management of metastatic GEA, the outcome of these patients remains dismal with a median overall survival of approximately 12 months (2). Chemotherapy represent the backbone of treatment for GEA; immunotherapy has recently shown some positive signal while targeted-therapies have been largely disappointing so far with only two approved drugs, trastuzumab and ramucirumab, monoclonal antibodies inhibiting HER-2 and VEGF-R2 respectively. The former is used as first line option in combination with chemotherapy in ERBB2 overexpressing/amplified metastatic tumors while the latter is used in the second line setting in unselected patients (2).

EGFR inhibition has been tested in combination with chemotherapy or alone in large randomized trials for first and second line GEA patients respectively (reviewed in (2)). The lack of patient selection based on EGFR expression or amplification in these studies, has probably played an important role in the negative outcome of these trials. Indeed, retrospective analysis of EGFR amplification status in the COG trial has demonstrated that a sub-population of patients that might benefit from the EGFR inhibitor gefitinib does exist, prompting to revisit the use of EGFRi in this context (3).

The study by Corso et al. (1) offers an opportunity to reflect on the promises and challenges ahead of us in the future re-development of EGFRi in GEA patients. The results described in the present study reinforce the notion that EGFR amplification has a strong negative prognostic value in both localized and advanced/metastatic GEA patients. These observations, coupled with the availability of effective EGFR inhibitors identify a potential group of GEA patients that might draw a significant benefit from EGFR blockade. Although there is general consensus surrounding the negative prognostic value of EGFR amplification in GEA, many questions regarding the predictive value of the biomarker remain open. The short answer to these questions is that EGFR amplification alone is not sufficient to identify patients who are likely to benefit from EGFR inhibition. Using patient data and in vivo experiments, Corso and colleagues (1) provide strong evidence suggesting that co-occurrence of EGFR and other receptor tyrosine kinase amplifications is associated with resistance to EGFRi. Chromosomal instability characterizes the vast majority of GEAs and co-amplification in RTKs such as EGFR, KRAS, MET, FGFR1&2, IGFR along with ERBB2 and VEGFA represents an intrinsic feature of these tumors (2) and a clear hurdle in the development of EGFR inhibitors in GEA (Figure 1A). The data presented by Corso et al. (1) echo results from a recent retrospective analysis of the REAL3 trial, where co-amplifications in RTKs were observed in a significant proportion of patients and correlated with lack of benefit from the EGFR monoclonal antibody panitumumab in combination with chemotherapy in advanced/metastatic GEA (4).

Figure 1. Roadmap to target selection in gastroesophageal adenocarcinomas (GEA).

Panel (A) summarizes frequency of common copy number alterations and single nucleotide variants and potential therapeutics in chromosomal unstable GEA. (B) Work-up of GEA patient candidate to EGFRi. Target NGS or low-pass WGS on tissue or cell-free DNA allows the identification of patients whose tumors carry EGFR amplification (positive biomarker) and lack of other RTKs that would hamper response to EGFRi. Potential therapeutic options for selected patients include dual EGFR inhibition, combination of EGFR inhibitors and immunotherapy or specific chemotherapeutics.

IHC= immunohistochemistry; CNA= copy number aberration; SNV single nucleotide variant; amp= amplification; RTK= receptor tyrosine kinase; EGFRi= epidermal growth factor receptor inhibitors; NGS= next-generation sequencing; WGS= whole genome sequencing.

Taken together, these observations highlight the paramount importance of molecular ultra-selection in the definition of GEA patients who might be candidate to EGFR inhibition. From a technical prospective, the use of targeted next generation sequencing or low-pass whole genome sequencing on tissue and/or liquid biopsies might help the simultaneous identification of EGFR amplification (positive biomarker) and lack of other RTK amplifications such as KRAS or MET (negative biomarkers), streamlining the selection of the right patient (4).

Precision oncology relies on the identification of the right treatment for the right patient. Besides shedding insights on patient selection, the results presented in the current article (1) also improve our understanding of EGFR targeting in GEA. Using randomized pre-clinical trials in PDXs, the authors show that dual EGFR inhibition with monoclonal antibodies and small molecules targeting EGFR is superior to either of these therapeutics used alone (1). Given feasibility and safety data from phase I trials (5) support the pre-clinical results presented by Corso and colleagues (1), dual EGFR inhibition appears as a sound approach for the development of combinatorial approaches and might represent a better option compared to combining EGFR inhibitors with chemotherapy.

The authors did not include chemotherapy in their pre-clinical studies in order to avoid any confounding effect that the addition of chemotherapeutics might have had on the interpretation of their results. Although the combination of EGFRi with fluoropyrimidine and oxaliplatin chemotherapy has been associated to long-term responses in some GEA patients (6), it is worth noticing that not all the chemotherapy agents commonly used in GEA represent a good therapeutic partner to combine with EGFRi. Indeed, clinical and pre-clinical data from GEA patients and patient-derived organoids (PDOs) suggest that combining EGFRi with epirubicin, a chemotherapy agent commonly used as standard of care in GEA, causes antagonisms and paradoxical increase in cell viability (4).

Using PDXs, Corso and colleagues also show that inactivating mutations in TSC2, a critical negative regulator of mTORC1, are responsible for resistance to EGFR inhibitors and suggest that the combination of everolimus (an mTOR inhibitor) with erlotinib might overcame primary resistance (1). Given the frequent co-occurrence of EGFR amplification and TSC2 inactivating mutation in GEA (https://www.cbioportal.org), these data have significant implications for patient selection and pathway inhibition in future studies.

Taken together, all these data highlight the importance of using patient-centered pre-clinical models (PDXs and PDOs) in the drug discovery trail, especially in those situations such as EGFR amplification in GEA, where commercially available cell lines are limited or not available.

In summary, the study by Corso and colleagues (1), along with other recent data in the field (3,4,6), broaden the reach of precision anti-cancer medicine to GEA, highlighting novel mechanisms of sensitivity to molecularly targeted therapeutics in selected populations and will contribute to reshape the selection and therapeutic exploitation of EGFR amplified GEAs. Unfortunately, none of the tools and the pre-clinical models used for patient selection in these recent studies were available when several landmark trials of EGFR inhibitors in GEA were designed and conducted more than ten years ago. The study by Corso and colleagues (1) highlight the promise of forward and reverse translation in precision oncology but also underscores some of the challenges ahead. Molecular (ultra)selection of patient for EGFR inhibitors or other targeted therapies in GEA appears as a critical step for accurate patient selection (Figure 1B) but will inevitably narrow down the number of patients eligible for such therapies; affecting the speed of recruitment and the sustainability of clinical trials in this setting. Strategic alliances between pharmaceutical companies and large international networks of academic investigators will represent a key for the feasibility and the success of molecularly driven trials in GEA.