Investment lessons · EGFR

The second act of EGFR

Tagrisso has generated $40B+ in the EGFR-mutation market. Patient data shows 5× more patients with amplified EGFR than with activating mutations, but amplified EGFR is a team player, which is why EGFR antibodies underperformed. Bispecific antibodies can address this market; the question is which product will win it.

EGFR case study · by Pawel Zawadzki, PhD

$40B+
Cumulative revenue generated by EGFR inhibitor Tagrisso (osimertinib), 2015–2025
The case

The expected success story

EGFR is one of the most powerful oncogenes, and it represents a beautiful success story of precision oncology.

Is a new gold rush about to start in the EGFR space?

Patient data shows the EGFR market could be massively expanded.

Finding 1

What the patient data revealed

EGFR is a great drug target.

  • Activating EGFR mutations are well understood and Tagrisso has won that market, currently generating over $7B/year.
  • But there are 5× more patients with amplified EGFR compared to ones activated by mutations.
  • Monoclonal antibodies targeting EGFR delivered clinical benefits, yet they never reached the potential proportional to the size of the market.

EGFR alterations across tissues

EGFR gain-of-function mutations and amplifications across tissues
Figure 1. GoF (Gain-of-Function) mutation; high amplification (≥7 additional EGFR gene copies); low amplification (2–6 additional gene copies).
Finding 2

What the patient data revealed

The comparison of mutated to amplified EGFR patients, revealed that amplified EGFR is not a solo-driver.

  • mAbs targeting EGFR were expected to match Tagrisso, yet they underperformed as amplified EGFR is a team player.
  • The concept of amplified EGFR being a team player is being validated by EGFR-MET and EGFR-LGR5 bispecific antibodies.
  • The big question is: which product will win the EGFR amplified market?

Mutated vs amplified EGFR

Mutated EGFR as a solo driver vs amplified EGFR with co-activated drivers in lung cancer
Figure 2. In lung cancer, mutated EGFR is a solo driver, while amplified EGFR requires supercharging by other players.
The take-home message

EGFR amplifications = opportunity

Take-home 01

Mutation vs amplification

Patient data confirms the extreme addiction of tumors to EGFR. But mutation ≠ amplification, explaining the underperformance of monoclonal antibodies and suggesting that BiAb might have a massive impact in the space.

Take-home 02

EGFR needs supercharging

BiAb can exploit the mechanisms used by tumors to supercharge EGFR signaling. EGFR-MET is a validation of what was obvious, but patient data suggest that the EGFR-MET product will not win this space.

Recommendations

Consult patient data for reliable outcomes

01

Mutated EGFR is such a strong driver

Therefore, no other supercharging is required.

02

Mutation ≠ amplification

In patient data, you can measure what other drivers are co-activated when EGFR gets amplified.

03

Patient data informs BiAbs design and winning strategy

Select highly amplified (>7 additional EGFR copies) patients for your initial trials to maximize the therapeutic window. Then, from patient biopsy data, select the second target to win the space.

Medicines intended to work in patients should be developed with patient data in mind.

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