The challenge of understanding treatment sequencing in oncology market research

As an oncology market researcher, I often find myself asking questions about sequencing of oncology treatments, particularly when a well-established later-line therapy shows benefit in an earlier-line clinical trial.  A few recently released clinical trials raise the sort of knotty sequencing issues that oncologists sometimes face.

• The BRUIN CLL-313/314 trials (https://www.fiercepharma.com/pharma/compelling-results-eli-lillys-jaypirca-advances-one-step-closer-first-line-use) compare the non-covalent Bruton’s tyrosine kinase (BTK) inhibitor Jaypirca (pirtobrutinib) to the combination of bendamustine and rituximab, and to the covalent BTK inhibitor Imbruvica (ibrutinib), respectively, in the first-line treatment of patients with CLL.  Pirtobrutinib was shown to be superior to bendamustine + rituximab and non-inferior to Imbruvica.
• The MARIPOSA trial (https://www.nejm.org/doi/full/10.1056/NEJMoa2503001) compares the combination of the antibody Rybrevant (amivantamab) and the tyrosine kinase inhibitor (TKI) (lazertinib) to the current standard of care, the TKI Tagrisso (osimertinib), in the first-line treatment of patients with EGFR-mutant metastatic non-small cell lung cancer.  Recently published data show an overall survival advantage for the combination of amivantamab and lazertinib.

While both of these trials seem likely to lead to first-line approvals, we should anticipate a few criticisms from oncologists:

• One concern, which we have heard frequently in market research interviews, is that moving an established later-line therapy into an earlier line can mean patients lose a potential line of therapy.  There is evidence that pirtobrutinib is effective in patients who have seen therapies such as the current standard agents acalabrutinib or zanubrutinib, but there is no evidence that the reverse is true.  Similarly, the combination of amivantamab and lazertinib can be used after treatment with osimertinib but not vice versa.
• Pirtobrutinib was compared to an obsolete standard of care in the BRUIN CLL-313 trial.  This can sometimes be unavoidable, given the time it takes to run clinical trials, especially in more slowly-progressing diseases, but it means that trials sometimes may not answer a question anyone is asking.  The BRUIN CLL-314 trial shows that pirtobrutinib is non-inferior to ibrutinib, which is an “other recommended option” in the most recent NCCN guidelines for CLL (v3.2025).  The second-generation BTK inhibitors acalabrutinib and zanubrutinib have largely replaced ibrutinib as covalent BTK inhibitors of choice and are the preferred first-line BTK inhibitors in the most recent NCCN guidelines.
• In the MARIPOSA trial, amivantamab/lazertinib did show a survival benefit over osimertinib, but in the trial publication, the authors note that there was no crossover in the trial due to the lack of approval for amivantamab/lazertinib at the time the study was started.  However, amivantamab/lazertinib has since become a standard second-line regimen.  MARIPOSA thus doesn’t really answer the question of whether patients live longer using amivantamab/lazertinib in the front line as opposed to starting with osimertinib and moving to amivantamab/lazertinib in the second line.

This situation raises several issues for oncology marketers who wish to understand the logic of sequencing.  Broadly speaking, we have encountered two broad perspectives on this issue from oncologists:

• The best therapy should always be used first, because you never know whether patients will be able to receive further therapy.
• If patients are able to receive multiple lines of therapy, it doesn’t matter what sequence they are treated in, since they will eventually see all of the effective therapies.

For some diseases, like CLL, in which oncologists expect to treat patients with several lines of therapy over a longer time, they may be more inclined to follow the second strategy, since patients can expect to live for years.  In such a case, oncologists may be reluctant to shift a medication into the first line unless it is shown to improve overall survival, ideally in a crossover trial.

In the absence of clear answers from clinical trials, oncologists will likely seek guidance from KOLs, as guidelines may be non-committal.  Marketers should also pay attention to secondary factors, such as tolerability, or even tertiary factors such as convenience:  osimertinib is oral and well-tolerated, while amivantamab/lazertinib requires visits to the clinic for infusions and a more complicated regimen.