Once again, Chicago saw the gathering of oncologists to discuss the latest developments in cancer. This year, considerable emphasis was placed on antibody-drug conjugates (ADCs), with several sessions dedicated exclusively to this technology. Whilst outcomes remained the primary focus, a pervasive theme could be detected throughout the five-day gathering and that was biomarkers.
Biomarkers: what do we mean?
– The term “biomarkers” can be broadly clustered into four categories: molecular, histologic, radiographic and physiological.
– They can also be used for a range of purposes, from identifying targets, to measuring effects and quantifying outcomes.
– However, their expression profiles can vary significantly in oncology, based on time, location, and tumor stage, as the cancer intuitively tries to evade eradication and continue to grow, modulating its form and function along the way.
– Many presentations and abstracts, at their core, relied on biomarkers to tell their story and focus the audience on the next horizons that must be crossed in solid and haematologic cancers; from detecting circulating DNA (ctDNA) in liquid biopsies, to targeting specific antigens on cells.
Biomarkers: what are the benefits?
Successes
– Some of the biggest standout moments came, not from the merger-rife ADC world or even advanced therapy medicinal products (ATMPs), but from the workhorse of the pharma stable: the small molecule.
– Lorbrena (lorlatinib), or Lorviqua in Europe, showed impressive five-year data from its CROWN trial in Stage IIIb/IV NSCLC for patients with an ALK mutation: an unprecedented level of PFS for a drug in late-stage NSCLC.
– Tagrisso (osimertinib), meanwhile, showed an equally impressive multi-year PFS advantage for patients in its LAURA trial in Stage III NSCLC for patients with an EGFR mutation, again setting new standards in this population.
– Both elegantly demonstrated the quality of outcomes that can be derived from targeting the right biomarker with the right product. Although, the lack of mature overall survival (OS) will remain a challenging topic for discussion with HTA bodies in some markets.
– ASCO also showcased some of the new biomarker-focused technologies coming to oncology, with Moderna/Merck’s three-year update on its mRNA neoantigen vaccine (V940) Phase 2b program in high-risk melanoma. It was revealed that V940’s addition to pembrolizumab has begun to show statistical significance in RFS (recurrence-free survival) and DMFS (distant metastasis-free survival), and an emerging trend in OS favouring the combination.
– Enhertu (trastuzumab deruxetecan) also highlighted biomarkers, but in a subtly different manner, by revealing for the first time that even cancers with “low” or “ultralow” expression of HER2 can be effectively treated; demonstrating positive outcomes in the DESTINY-Breast06 trial.
Learnings
– Although ADCs were clearly a high priority topic for discussion at ASCO, the more traditional forms of drug mechanisms continued to hold their own as effective means of tackling cancer – especially when coupled to a biomarker.
– Individualised neoantigen therapies (INTs) are delivering on their scientific promise; allowing physicians to deliver a precision medicine-based approach on an individual, tumour-specific level based on a patient’s own cancer. If this can be replicated across tumour types and in larger trials, this could mark a new paradigm shift in how we approach adjuvant therapy, to provide long term protection against relapse or recurrence.
– Finally, the Enhertu case study could shape how we think about biomarkers’ expression levels and leveraging drugs to treat patients with residual levels of expression – if we can detect them.
The future
– “Ultralow” levels of a biomarker necessitate “ultrasensitive” assays to differentiate patients with no expression from those with a minimal level, to ensure that these high-cost therapies are used appropriately. Importantly, the investigators noted that HER2-negative patients would not benefit from the product; emphasizing the need for certainty in detecting the ultralow end of signalling.
– Indeed, pathologists have remarked that this level of expression pushes the boundaries of what the human eye can feasibly identify, so the imminent launch of new assays, including one recently launched by Roche, is sorely needed. It will be interesting to see how various non-clinical stakeholders, like payers, focus on the need for such diagnostics and how equitable access will be guaranteed.
– Even within resoundingly positive trial programs, there are still patients that seemingly do not respond, whilst others show complete responses with minimum residual disease (MRD) detectable, suggesting that other, unknown biomarkers are at play.
– Further advances in next generation sequencing (NGS) and post-hoc analyses of existing datasets from trials will be necessary, to shed further light on the molecular signals that could be used to predict response level.
Biomarkers: what barriers are we seeing?
Challenges
– The core issue with the use of biomarkers for targeting purposes in oncology, is that they rarely stay static, nor do they typically exist solely on the surface of tumors. Indeed, physicians discussed that primary and metastatic tumours also differ in their biomarker makeup, confounding the topic further.
– Phase 2 and 3 readouts for ADCs are now increasingly showing that delivering cytotoxic payloads, specifically to tumour cells, is perhaps more challenging than first anticipated, given tumours’ ability to rapidly develop resistance mechanisms to counter the ADC.
– Successes with some of the early entrants, including Enhertu (trastuzumab deruxetecan) and Padcev (enfortumab vedotin), are subsequently not materialising as commonly as physicians and the industry would likely hope.
– Coupled to this, it is becoming clear that some of the biomarkers being targeted by new products are distributed too broadly, or the chemistry of the ADCs is not yet advanced enough to avoid off-target effects: all ADC products’ toxicity profiles remain a hot topic for physicians.
– Somewhat surprisingly at several points over the meeting, key opinion leaders (KOLs) voiced their scepticism regarding some of the more well-known ADCs moving into new tumours or earlier lines of therapy, based on sub-optimal outcomes in other tumours and lines of therapy.
– Such hesitancy, if noted by lead investigators typically based in large, well-funded, academic centres, could manifest even more challenges in community hospitals, or for physicians in countries with less exposure to the use of ADCs.
Learnings
– Each element of the ADC: the antibody (plus its target), the linker and the payload, is still being worked out and understood by the scientific and clinical community; we are still most assuredly in the early days of this exciting technology.
– Safety and toxicity associated with ADCs is a continuing and mounting concern, with each new antibody/ linker/payload reveal at ASCO bringing its own specific spectrum of unwanted side effects; often driven by binding at sites outside the tumour itself.
– With regards to efficacy, a similar trend emerged at ASCO: not all ADCs are created equal, resulting in products being seen as “a” potential new option, as opposed to “the” definitive new standard of care in a particular line of therapy and cancer.
– The lesson here is that perhaps this product is best suited for a specific point in the treatment sequence, or that a specific biomarker exists at this time point, that is necessary for the drug to optimally function.
– Blenrep (belantamab mafodotin), for instance, was a product that had to be withdrawn at the request of the FDA, given its lack of proven efficacy in 3L+ multiple myeloma in the DREAMM-3 trial. However, the same drug appears to have awoken from its nightmare courtesy of the DREAMM-7 and DREAMM-8 trials that were discussed at ASCO, revealing a role for the BCMA-targeting ADC in patients after their first relapse; suggesting that timing the use at this point in the disease is a more valid approach for targeting.
The future
– Currently, over 90 active trial programs are looking at a range of antigen targets, with TROP2 the most frequently investigated, followed by HER2, B7H3 and HER3 – some of which are entirely novel, whilst others are focusing on targets that have already been explored.
– However, as covered repeatedly at ASCO, not all ADCs are made equal, as has been the case with the PD-(L)1 class of products. We may yet uncover more paradigm-changing products within a target class that has already been validated, or challenged clinically.
– Further, timing/sequencing of products to match the tumour’s location, peak expression profile, and cellular makeup to increase potency, is an area that requires further investigation.
– Reducing the scale of the adverse event profile is a clear goal for these future ADCs, to avoid deterring physicians and patients from selecting the products, and improving payers’ clinical assessments of benefit: risk profiling.
– Multitarget-specific ADCs represent a potential attractive solution to the issues presented by current ADCs, given that single biomarkers are often expressed in non-tumour tissues and organs. So, focusing on a combination of biomarkers could be a way of increasing specificity.
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