Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric Carcinoma: Results of the Proof-of-Concept iMYC Study

Round 1

Reviewer 1 Report

Ibrutinib in c-MYC and HER2 Amplified Oesophagogastric 2 Carcinoma: Results of the Proof-of-Concept iMYC Study

In the current manuscript the authors provide results of a proof of concept phase II trial exploring safety and efficacy of ibrutinib in c-MYC /Her2 amplified oesophagogastric cancer including squamous cell carcinoma and adenocarcinoma. The authors should be congratulated for their efforts to explore this approach in a biomarker-defined subset of esophagogastric cancer.

The manuscript is well written, I only have some minor remarks:

• it seems unusual that Her-2 directed treatment (trastuzumab) was not mandatory before study treatment in patients with Her-2 positive adenocarcinoma. Authors should comment on this.

• Authors should add a short rationale for their ibrutinib dosage, as different dosages are used in different haematological diseases.

• given the high number of patients with detection of a c-MYC amplification it is surprising that the planned number of patients (n=9 for stage 1) could not be recruited. Are there any explanations for the high rate of patients that could not be included despite the proof of the c-MYC/Her-2 amplification?

• As this was an early phase II proof of concept design some more details on safety assessment (including involvement of the IDMC) should be included, where there any specific safety endpoints?

• Section 2.3: According to the manuscript Section 2.1 patients with c-MYC and/or Her-2 amplification were eligible. In section 2.3 it is written that patients with “a c-MYC amplification and a c-MYC ratio of ≥ 2.5 were considered eligible” with no status about required Her-2 results in the screening FISH analysis. Below it is stated that only patients eligible for main study entry were tested for Her-2 status. Thus, the workflow is unclear to me. Where all patients tested in parallel for Her-2 and c-MYC or was Her-2 testing restricted in comparison to c-MYC testing?

Author Response

• it seems unusual that Her-2 directed treatment (trastuzumab) was not mandatory before study treatment in patients with Her-2 positive adenocarcinoma. Authors should comment on this. 

Thank you very much for this comment. We have included the following in the results section of the manuscript: The two patients who were not previously treated with trastuzumab experienced disease progression during or within 6 months of neoadjuvant/adjuvant therapy or definitive chemoradiation and therefore their neoadjuvant/adjuvant therapy was counted as first line treatment of advanced disease.

• Authors should add a short rationale for their ibrutinib dosage, as different dosages are used in different haematological diseases.

Thank you very much. The 560mg ibrutinib dosage was chosen in line with other phase III studies using ibrutinib in solid tumours e.g. phase III RESOLVE study evaluating ibrutinib in combination with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer (NCT02436668) 

• given the high number of patients with detection of a c-MYC amplification it is surprising that the planned number of patients (n=9 for stage 1) could not be recruited. Are there any explanations for the high rate of patients that could not be included despite the proof of the c-MYC/Her-2 amplification?

To gain a broad spread of patients with c-MYC and/or HER2 amplification the protocol also stipulated that within the first projected recruitment of 9 patients, at least 4 will demonstrate c-MYC amplification. The remaining 5 will show either c-MYC or HER2 amplification or co-amplification of both (We have added this to the manuscript)

Additionally, patients were often pre-screened during their previous line of therapy however by the time of the need for a change in treatment, when entry to the iMYC trial could be considered, they may not have been eligible at this stage. Furthermore, the iMYC testing usually took a couple of weeks to come back however often patients’ archival tissue had to be retrieved from other centres which may have taken a further 2-4weeks and therefore slowed down the process. As we have seen from the results of the trial, patients with OG cancer often progress quickly after first line treatment and therefore if there were delays in the MYC testing, patients often needed to start an alternative treatment quickly. Finally, during the period that recruitment was paused until the IDMC could convene to assess and advise upon the bleeding events that had occurred, many patients that were previously prescreened had started on other treatments already during this time.

• As this was an early phase II proof of concept design some more details on safety assessment (including involvement of the IDMC) should be included, where there any specific safety endpoints? 

Thank you. The only safety endpoint was safety and tolerability of ibrutinib treatment in advanced oesophagogastric cancer (adverse events according to CTCAE v 4.0). The IDMC was extensively involved with the study and as describe in the manuscript gave recommendations in light of the bleeding events whereby the trial eligibility criteria were updated. In addition, we were also in receipt of updated safety data from the drug manufacturer throughout the duration of the study.

• Section 2.3: According to the manuscript Section 2.1 patients with c-MYC and/or Her-2 amplification were eligible. In section 2.3 it is written that patients with “a c-MYC amplification and a c-MYC ratio of ≥ 2.5 were considered eligible” with no status about required Her-2 results in the screening FISH analysis. Below it is stated that only patients eligible for main study entry were tested for Her-2 status. Thus, the workflow is unclear to me. Where all patients tested in parallel for Her-2 and c-MYC or was Her-2 testing restricted in comparison to c-MYC testing?

Thank your very much for highlighting this. Local HER2 testing results were sufficient for trial entry, central testing was not mandated within the protocol. Therefore, patients were mostly enrolled with their local HER2 result unless there was a reason that this needed to be tested centrally. We have now clarified this in the manuscript. 

Reviewer 2 Report

This paper reports not only a negative trial but also a trial which aborted for some reasons. 

Minor comments: 1/please delete figure 2, as it does not add value to the paper, 2/ In the limitation part of the discussion section, please insert a few lines on the reason of early termination of the study

Author Response

1/Please delete figure 2, as it does not add value to the paper

Thank you very much. This figure has been moved into supplementary data.

2/ In the limitation part of the discussion section, please insert a few lines on the reason of early termination of the study

Thank you very much. Added the following sentence into discussion: Due to the Covid-19 pandemic and loss of pre-screening capacity in our cytogenetics department to undertake FISH testing, the trial was closed early.