Bemcentinib NSCLC data continues to impress

Update | 19 November 2019

Share this note

In an oral presentation at SITC, new results from Cohort A of the Phase II NSCLC trial with BerGenBio’s selective AXL inhibitor bemcentinib and pembrolizumab confirms the potential of the combination. 90% of the 44 evaluable patients in the cohort had PD-L1 low/negative tumours, and yet the objective response rate (ORR) was 25%; <10% would have been expected with pembrolizumab monotherapy. In those patients, who were AXL+ using a new composite score, the ORR was 33% compared to 7% in those classed as AXL-. Cohort A is in immuno-oncology (IO) naïve patients, and there are also two other cohorts in IO-refractory patients ongoing, the results of which will determine the design of the randomised Phase II study planned to start in 2020. We maintain our valuation of BerGenBio at NOK3.21bn (NOK53.13/share).

Year-end: December 31201720182019E2020E
Sales (NOKm)0.02.3 8.70.0
Adj. PBT (NOKm)(182.2)(197.7) (198.1)(266.9)
Net Income (NOKm)(182.2)(197.7) (198.1)(266.9)
Adj. EPS (NOK)(4.0)(3.6) (3.4)(4.4)
Cash (NOKm)370.4360.4 234.376.1*
EBITDA (NOKm)(183.5)(194.3) (200.6)(264.5)
Source: Trinity Delta; Note: *2020E cash includes a NOK100m capital raise. Adjusted numbers exclude exceptionals.
  • Phase II NSCLC data gets more compelling The results from Cohort A of the ongoing Phase II NSCLC trial consistently indicate that bemcentinib enhances the activity of pembrolizumab, especially in those patients expected to have only a limited clinical benefit as their tumours are PD-L1 low/negative. The ORR of the 44 evaluable patients is currently 25% (9 patients still on therapy) so the trial has met the primary efficacy endpoint (ORR ≥25% of evaluable patients). This response is notable as an ORR of <10% would be expected with pembrolizumab monotherapy, as 90% of patients had PD-L1 low/negative tumours.
  • New AXL composite biomarker score identified Detailed gene expression analysis of tumour tissues indicated that AXL activity in both tumour and immune cells is necessary to best identify those patients likely to benefit from bemcentinib and pembrolizumab. When the patients are stratified using the new proprietary composite AXL Score, there was a 33% ORR in the AXL+ patients and only a 7% ORR in the AXL- patients, and median PFS was 8.4 and 2.9 months respectively.
  • Data from other Cohorts to determine Phase IIb design These data clearly justify the further development of bemcentinib in combination with pembrolizumab in second-line AXL+ IO-naïve NSCLC patients. But, BerGenBio is prudently waiting for data from Cohorts B and C in IO-relapsed patients before finalising the design of the Phase IIb trial. The Phase IIb study is expected to start in 2020.
  • Valuation unchanged at NOK53.13/share (NOK3.21bn or $378m)  BerGenBio’s share price has risen by over 30% during the last three months, but our valuation still suggests the potential of bemcentinib is under appreciated. The company is keeping a tight control of its expenses and had a cash position of NOK290m at the end of Q319, which we estimate will allow it to operate into Q420.


19 November 2019

Market CapNOK1.04bn
Enterprise ValueNOK747m
Shares in issue61.1m
12-month rangeNOK11.50-32.80
Free float60.6%
Primary exchangeOslo
Other exchangesN/A
Company CodeBGBIO
Corporate clientYes

Company description

BerGenBio is a clinical-stage, biopharmaceutical company based in Bergen, Norway and Oxford, UK. It is developing innovative therapies for aggressive cancers by way of inhibiting the AXL signalling pathway. The lead oncology compound, bemcentinib, is in multiple Phase II trials.


Mick Cooper PhD
+44 (0) 20 3637 5042

Lala Gregorek
+44 (0) 20 3637 5043

Dr Matthew Krebs, a principal investigator for the Phase II study in NSCLC with bemcentinib in combination with pembrolizumab, gave an oral presentation of the latest data from the trial, including new biomarker data, at the SITC (Society for Immunotherapy of Cancer) 2019 meeting. The growing body of data adds weight to the hypothesis that bemcentinib has the potential to significantly enhance pembrolizumab activity and become a valuable treatment in NSCLC.

Clinical trial overview

A schematic of the clinical trial design of the Phase II study BGBC008 in NSCLC with bemcentinib in combination with pembrolizumab is summarised in Exhibit 1. The data presented at SITC 2019 was from Cohort A in immuno-oncology (IO) naïve patients. There are an increasing proportion of patients receiving PD-1/PD-L1 inhibitors in the first-line setting, which is why BerGenBio added Cohort B (previously treated with a PD-1/PD-L1 inhibitor, recruitment ongoing) and Cohort C (previously treated with PD-1/PD-L1 inhibitor in combination with platinum-chemotherapy, recruitment about to start) to the study. That said, the IO-naïve setting in second-line NSCLC could still be an attractive opportunity for bemcentinib as PD-1/PD-L1 inhibitors have limited efficacy in patients with PD-L1 low or negative tumours, approximately two thirds of NSCLC patients.

Exhibit 1: Clinical trial design of Phase II study in NSCLC with bemcentinib in combination with pembrolizumab
Source: SITC 2019, Matthew Krebs et al

90% of patients in Cohort A had low or negative PD-L1 tumours (TPS<50%, Exhibit 2). Based on Merck’s Phase I KEYNOTE 001 and Phase III KEYNOTE 010 studies with pembrolizumab monotherapy in NSCLC, an ORR between 8% and 10%, and a mPFS between 2.1 months and 3.9 months would be expected without bemcentinib. For reference, patients with high PD-L1 tumours (TPS≥50%) in the KEYNOTE 010 trial achieved an ORR of 30% and mPFS of 5.2 months.

At the data cut-off point of 30 September 2019 for the SITC presentation, 44 of the 50 recruited patients were evaluable and nine patients were still receiving bemcentinib in combination with pembrolizumab.

Exhibit 2: Summary of patient disposition and biomarkers
Source: SITC 2019, Matthew Krebs et al

Efficacy and safety data

Overall the ORR was 25% among the 44 evaluable patients (Exhibit 3), which is significantly higher than would be expected with pembrolizumab monotherapy, given the proportion of patients with PD-L1 low or negative tumours (as discussed above). The achievement of an ORR of ≥25% of evaluable patients also means that the Phase II study has formally met its primary efficacy endpoint.

In the 15 patients classed as being AXL+ using a new composite score, the ORR was 33% but only 7% with the 15 patients classed as being AXL-.

Previously, patients were classified as being AXL+ or AXL- based only on AXL expression within a tumour (using immuno-histochemistry, IHC); the new composite approach also takes into account AXL activity in myeloid immune cells (see below). In the data published at the WCLC (World Congress on Lung Cancer) 2019 meeting on 8 September, the ORR in the 15 AXL+ patients was 40% and 15% for the 13 AXL- patients, with the patients classified using the previous method (tumour-only AXL expression). The new classification system appears to identify those patients likely to benefit from treatment with bemcentinib with greater specificity, though this needs to be confirmed with prospective analysis.

Interestingly, the level of PD-L1 expression does not appear to correlate with better response rates, although the number of patients, especially those with PD-L1 high tumours, is limited.

Exhibit 3: Waterfall plot of best change in sum of target lesions (from baseline) of patients and response rates with different biomarkers
Source: SITC 2019, Matthew Krebs et al

The overall mPFS was 4.1 months (Exhibit 4), which again is better than what would be expected with pembrolizumab monotherapy. mPFS in the KEYNOTE 010 trial was 3.9 months, however 40% of the patients were PD-L1 high, 60% were PD-L1 low and there were no PD-L1 negative patients.

There is a clear separation of the Kaplan-Meier curves of PFS for patients classed as AXL+ and AXL- using the new composite system, with mPFS of 8.4 months and 2.9 months respectively. The mPFS in AXL+ patients is based on only 15 patients, but it compares very favourably to the 5.2 months observed in PD-L1 high patients in the KEYNOTE 010 trial.

Exhibit 4: Kaplan-Meier curve of PFS for patients with AXL +ve/-ve composite scores
Source: SITC 2019, Matthew Krebs et al

Bemcentinib in combination with pembrolizumab continued to be well tolerated with no composite toxicity observed (Exhibit 5). The adverse event profile of the two drugs together still appears to be very similar to that seen with pembrolizumab monotherapy.

Exhibit 5: Treatment related adverse events observed in Phase II study
Source: SITC 2019, Matthew Krebs et al

There were nine patients still on treatment at the end of September (time of data cut off for the presentation), so the data is still maturing and we expect more data from the trial to be reported in H120.

Biomarker analysis

Previous biomarker analysis in the Phase II NSCLC trial had only focused on AXL expression in tumour cells. However, further analysis showed that, while there was a correlation between tumour AXL expression and responders, it failed to identify fully those likely to respond. Detailed analysis of gene expression of tumour tissue (including immune cells) showed that AXL expression (in tumour and immune cells), genes associated with the epithelial-mesenchymal transition (EMT) of tumour cells and activation of myeloid immune cells (eg. macrophages) were linked to a clinical benefit (Exhibit 6).

AXL is known to play important roles in the activation of both EMT (via Twist and Snail activation) and myeloid activation (including M2 macrophages via STAT1 signalling, see February’s Outlook note). Also, the two processes are linked to tumours evading immune surveillance. So, there is a strong scientific rationale for the tumours with EMT and myeloid activation gene signatures responding to treatment; bemcentinib overcomes immune escape of these tumours, allowing the cytotoxic T-cells without inhibition from PD-1 signalling to kill tumour cells.

Interestingly, other clinical studies are showing that a EMT gene signature, and AXL or TGF-β expression (produced by M2 macrophages) are associated with resistance to pembrolizumab treatment, such as the analysis of tumours samples from urothelial cancer patients in the KEYNOTE-052 study.

Slightly surprisingly, the expression of PD-L1 and IFN-γ were not predictive of a clinical benefit in the current NSCLC trial. PD-L1 is the main biomarker used to predict the likelihood of a patient benefiting from a PD-1/PD-L1 checkpoint inhibitor like pembrolizumab. Similarly, IFN-γ promotes a pro-inflammatory state within a tumour, in which cytotoxic T-cells are active, and has previously been shown to be predictive of a clinical response to PD-1 inhibition.

Exhibit 6: Volcano plot of the results of the gene expression analysis of three responders and three non-responders.
Source: SITC 2019, Matthew Krebs et al

Based on this analysis, BerGenBio devised the new composite AXL score to identify patients likely to benefit from bemcentinib and pembrolizumab treatment. Precise details of the test have not been disclosed, but it takes into account AXL expression in both tumour and immune cells.

The composite AXL score needs to be validated as a companion diagnostic tool, which will be done during the planned, randomised Phase II study due to start in 2020 and subsequent Phase III programme. The utility of the composite AXL score will also be assessed during the prospective analysis of patients in Cohorts B and C of the current Phase II trial.

Valuation and financials

We continue to value BerGenBio at NOK3.21bn (NOK53.13/share) or $378m. BerGenBio’s share price has increased steadily by over 30% during the last three months; nevertheless our valuation still suggests the shares are materially undervalued. The next expected catalyst for the shares is the presentation of new data from the Phase II study in AML with bemcentinib in combination with LDAC (low dose cytarabine) at the ASH (American Society of Hematology) meeting on 7-10 December.

We have revised our expectations to reflect the Q319 results and its tight control of expenses, as indicated in Exhibit 7. The company had a cash position of NOK289.5m, which we estimate will allow the company to operate into Q420.

Exhibit 7: Summary of changes to estimates
Source: Trinity Delta
Exhibit 8: Summary of financials
Source: Company, Trinity Delta  Note: The short-term debt in FY20 is indicative of the company’s funding requirement.




Trinity Delta Research Limited (“TDRL”; firm reference number: 725161), which trades as Trinity Delta, is an appointed representative of Equity Development Limited (“ED”). The contents of this report, which has been prepared by and is the sole responsibility of TDRL, have been reviewed, but not independently verified, by ED which is authorised and regulated by the FCA, and whose reference number is 185325.

ED is acting for TDRL and not for any other person and will not be responsible for providing the protections provided to clients of TDRL nor for advising any other person in connection with the contents of this report and, except to the extent required by applicable law, including the rules of the FCA, owes no duty of care to any other such person. No reliance may be placed on ED for advice or recommendations with respect to the contents of this report and, to the extent it may do so under applicable law, ED makes no representation or warranty to the persons reading this report with regards to the information contained in it.

In the preparation of this report TDRL has used publically available sources and taken reasonable efforts to ensure that the facts stated herein are clear, fair and not misleading, but make no guarantee or warranty as to the accuracy or completeness of the information or opinions contained herein, nor to provide updates should fresh information become available or opinions change.

Any person who is not a relevant person under section of Section 21(2) of the Financial Services & Markets Act 2000 of the United Kingdom should not act or rely on this document or any of its contents. Research on its client companies produced by TDRL is normally commissioned and paid for by those companies themselves (‘issuer financed research’) and as such is not deemed to be independent, as defined by the FCA, but is ‘objective’ in that the authors are stating their own opinions. The report should be considered a marketing communication for purposes of the FCA rules. It has not been prepared in accordance with legal requirements designed to promote the independence of investment research and it is not subject to any prohibition on dealing ahead of the dissemination of investment research. TDRL does not hold any positions in any of the companies mentioned in the report, although directors, employees or consultants of TDRL may hold positions in the companies mentioned. TDRL does impose restrictions on personal dealings. TDRL might also provide services to companies mentioned or solicit business from them.

This report is being provided to relevant persons to provide background information about the subject matter of the note. This document does not constitute, nor form part of, and should not be construed as, any offer for sale or purchase of (or solicitation of, or invitation to make any offer to buy or sell) any Securities (which may rise and fall in value). Nor shall it, or any part of it, form the basis of, or be relied on in connection with, any contract or commitment whatsoever. The information that we provide is not intended to be, and should not in any manner whatsoever be, construed as personalised advice. Self-certification by investors can be completed free of charge at TDRL, its affiliates, officers, directors and employees, and ED will not be liable for any loss or damage arising from any use of this document, to the maximum extent that the law permits.

Copyright 2019 Trinity Delta Research Limited. All rights reserved.