The past few years have seen a number of revolutionary modalities join the oncology landscape, such as antibody-drug conjugates (ADCs), bispecifics, KRAS inhibitors, and most recently, cancer vaccines.
These targeted therapies are shifting the way patients are treated in second-line cancer and beyond, with some also showing promising data in the frontline setting, but they do remain relatively nascent in this space.
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At the European Society of Medical Oncology (ESMO) congress 2026, held in Madrid, Spain, from 23 to 27 October, clinicians discussed the tolerability concerns associated with ADCs, bispecific and RAS inhibitors.
During a session focussing on managing toxicities of novel therapies, Dr Noemi Reguart, thoracic oncologist at the Department of Medical Oncology at Hospital Clínic de Barcelona, emphasised how the target, alteration, and mechanism of action (MoA) all shape a safety profile, adding that newer therapies and longer treatment durations bring evolving toxicities.
This is emphasised more when used in combinations, as some targeted therapies can cause serious toxicity when used together, or if administered too soon after immunotherapy, or with certain chemotherapies.
A better understanding of these candidates, as well as potential combinations they can be used in, is the next path forward for the space in certain situations without chemotherapy.
Chemotherapy disappearing from frontline
The first chemotherapy was approved for use in 1949, and while they were not initially used in frontline but instead as a last resort, it later became standard for many indications in these settings.
Today, the pendulum is swinging again, and not only in hot tumours including certain non-small cell lung cancers (NSCLC) and metastatic melanoma, where targeted therapies have displayed well-established benefit, but data are now showing their promise in cold tumours.
Hot tumours are those that are heavily infiltrated by immune cells, making them easier to target while cold tumours do not trigger a strong immune response or get infiltrated by immune-fighting T cells, making them more challenging to target.
Speaking to Clinical Trials Arena at ESMO, Dr Eleni Lagkadinou, VP of oncology early development at AbbVie, talked about data being presented by the sponsor, including the Phase I (NCT05029882) trial of ADC temab-A, which is being used in combination with Avastin (bevacizumab), a humanised monoclonal IgG antibody (mAb), in heavily treated advanced colorectal cancer patients.
At ESMO, AbbVie shared longer-term data, demonstrating an overall survival (OS) rate of 14.7 months in those who received the investigational combination compared to 10.2 months in the comparator arm, in which patients received standard of care (SoC) trifluridine/tipiracil. The combination is being investigated in a Phase III trial (NCT06614192).
“This will become a new way of treating oncology and will provide more options for our patients, which is important. Multimodality chemotherapy has been used for a long time and comes with a lot of safety considerations when different chemotherapies are combined,” Lagkadinou commented.
Lagkadinou added that the discovery of more biomarkers and targets has been key in moving beyond previous standard regimens.
“The benefit for patients is access to more tailored approaches, precision medicine-directed approaches. When we think of the safety profile, we move from this multimodality chemotherapy with the safety events these can cause to a safety profile we can better characterise and optimise on better schedules,” she added.
These novel combinations have also shown benefit in cold tumours, such as small cell lung cancer, which have historically been difficult to treat.
Dr Pedro Rocha, medical oncologist at Vall d’Hebron University Hospital, was a principal investigator (PI) in ZaiLab’s Phase Ib trial evaluating zocilurtatug pelitecan, an ADC, in combination with Tecentriq (atezolizumab), an immune checkpoint inhibitor (ICI) that blocks Programmed Death-Ligand 1 (PD-L1), with and without carboplatin as first-line treatment for extensive-stage small cell lung cancer (ES-SCLC).
The study found that in the doublet arm, which did not include chemotherapy, there was a confirmed objective response rate (ORR) of 81.8%, with a six-month progression-free survival (PFS) rate of 81.9%.
Median PFS has not yet been reached at a median follow-up of 10 months, with 10 of the 15 patients treated remaining free of disease progression or death at the data cutoff.
In comparison, SoC for first-line SCLC is a checkpoint inhibitor plus chemotherapy, which delivers a 60-70% response rate, a PFS of about five months, and is associated with Grade >3 treatment-related AEs around 60%.
As a result, Rocha agrees that regimens involving no chemotherapy could be phased out in the front line.
When asked by Clinical Trials Arena if he believed this could be the case on a broader scale, Rocha said: “If you were asking me that question two years ago, I would say no – that’s a crazy idea. But now with new data coming out, we are really approaching that phase that we are removing chemotherapy from first line. We will still use them in later lines, but it is definitely looking like we will be removing the chemotherapy from frontline.”
Ultimately, it is vital that these combinations show at least – if not more – comparative efficacy, but the removal of chemotherapy also means clinicians can be more conscious about adverse events (AEs) in patients.
“I believe that it’s also our responsibility as oncologists to control adverse events. Sometimes we are able to do that with nausea and other symptoms, but events such as neutropenia and thrombocytopenia are quite difficult to control or to predict. If you have a treatment without any of this toxicity, that will make our lives much easier,” Rocha added.
These two studies, amongst others presented at ESMO 2026, are showing an ongoing shift away from chemotherapy being used in the first-line setting for more indications, but more research will be needed to better understand what combinations of more novel therapies can be combined before it is seen on a broader scale across the sector.
While these therapies will always be used for patients who later progress, moving them away from the frontline in more indications is a significant shift for the sector as a whole, and a trend that is exciting investigators and clinicians alike.
