This year’s American Society of Clinical Oncology (ASCO) Annual Meeting set the agenda for oncology research, with cutting-edge research into topics as diverse as immunotherapy, the latest small molecule trials, and the growing role of AI in drug development.

Tens of thousands of oncologists gathered at Chicago’s McCormick Place for ASCO 2024 – but what research impressed them the most and what evidence backed a change in clinical practice?One such piece of research presented by Peter Borchmann MD, of the University Hospital of Cologne and Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, and German Hodgkin Study Group.Borchmann’s research showed that a cocktail of drugs known as BrECADD, including novel agents and Takeda/Pfizer’s Adcetris (brentuximab vedotin), is significantly more effective than the standard care cocktail known as BEACOPP.The German Hodgkin Study Group (GHSG) HD21 trial compared the BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone) chemotherapy regimen with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen in a positron-emission tomography (PET)-adapted approach in patients with advanced-stage classical Hodgkin lymphoma.BrECADD was associated with a four-year progression-free survival, reducing the risk of progression, relapse, or death by one-third.

Immunotherapy advances

Getting cancer immunotherapy to work in more patients and in hard-to-treat cancers remains one of the big challenges of modern medicine.ASCO provided some groundbreaking new data from established drugs, with AstraZeneca’s PD-L1 inhibitor Imfinzi (durvalumab) taking centre stage during Sunday’s plenary session.AZ unveiled interim results from ADRIATIC, the first Phase III trial to show benefit with immunotherapy in patients with limited-stage small cell lung cancer (LS-SCLC).This form of cancer is typically confined to one lung, and findings from Adriatic were described as the first new treatment option for this population in decades, although final results are still forthcoming.In the trial involving 530 patients, median overall survival with Imfinzi was 55.9 months versus 33.4 months on placebo, with results could establish the first new standard of care for 40 years.

There was also data from Bristol-Myers Squibb’s Yervoy (ipilimumab) in combination with BMS’ other immunotherapy Opdivo (nivolumab), two of the first checkpoint inhibitors approved that inhibit CTLA-4 and PD-1, respectively.

In macroscopic stage III melanoma, this combination in the neoadjuvant setting is also set to become a new standard of care, according to Phase III data from the NADINA trial.

Results showed the combination, followed by therapeutic lymph node dissection (TLND), reduced risk of progression, recurrence or death by 68% compared with TLND and adjuvant Opdivo alone, according to results simultaneously published in the New England Journal of Medicine.

The highly statistically significant results (p< .0001) were consistent across key subgroups.

AstraZeneca/Daiichi Sankyo’s antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan) also produced convincing results in tough-to-treat group of breast cancer patients.

Enhertu showed a clinically meaningful benefit for patients with HR-positive, HER2-low and HER2-ultralow metastatic breast cancer following one or more lines of endocrine therapy in the Phase III DESTINY-Breast06 trial.

In the primary analysis of DESTINY-Breast06, results showed Enhertu reduced the risk of disease progression or death by 38% by blinded independent central review (BICR) versus chemotherapy in patients with HER2-low. Median PFS was 13.2 months in the Enhertu arm, compared with 8.1 months for chemotherapy.

Commenting generally on what constitutes a success at ASCO, Jerry McMahon, CEO of Cambridge-UK based STORM Therapeutics, said only big improvements in survival will create a buzz and catch the eye of the oncology experts gathered in Chicago.

He said: “Success now is all about big improvements in progression free survival and overall survival. For many years we had new therapies that made advances but the progression free survival did not last long or translate into overall survival benefit for various reasons.”

Cell therapies

Cancer cell therapies are another innovation in oncology from the past decade, and pharma and biotech companies are working to improve issues such as response rates and lack of efficacy in solid tumours.Chimeric antigen receptor T-cell (CAR-T) therapies have been limited to use in blood cancer because of the receptor used in the first approved therapies, and the fact they lack the staying power to infiltrate the next of defences surrounding solid tumours.This year saw the first FDA approval of a cancer cell therapy that is able to take on solid tumours, with them giving the green light to Iovance Biotherapeutics’ tumour-infiltrating lymphocyte (TIL) therapy Amtavgi (lifileucel) in February for advanced melanoma after treatment with a PD-1 inhibitor and a BRAF inhibitor if a BRAF V600 mutation is present.There was further data from Amtavgi at ASCO, where a Phase II TILVANCE-301 trial testing it in combination with the mainstay PS-1 from Merck & Co, Keytruda (pembrolizumab) showed an encouraging response rate in immunotherapy-naive advanced melanoma.Low response rates have been an issue with checkpoint inhibitors since the get-go and the complete response (CR) rate with the combination of 30.4%, and objective response rate of 65.2%, was enough to justify the ongoing Phase III trial, TILVANCE-301.

Presenting the results, Sajeve S. Thomas, of the Orlando Health Cancer institute said this was probably the highest CR rates seen from cell therapies, with other studies showing CRs of around 15%-20%.

However, Sunandana Chandra, MD, MS, of the Robert H Lurie Comprehensive Cancer Centre of Northwestern University, warned this must be balanced against side effects including long-term immune-related adverse effects.

Giusy Di Conza, head of research at cancer biotech iOnctura, noted a Phase I trial showing AbelZeta’s C-CAR031, a novel glypican-3 (GPC-3) CAR-T, produced encouraging results in a cohort of 22 patients with advanced hepatocellular carcinoma.

“The progress in cell therapies presented at ASCO is incredibly promising. We have seen, for example, encouraging data on novel CAR-T cells targeting a liver-specific antigen (GPC3) achieving 50% ORR and 90% DCR in heavily pretreated metastatic liver cancer patients.

“These therapies, together with TIL, TCR-T and NK cell therapies, are breaking new ground, especially in solid tumours, which have traditionally been challenging to treat with cell-based approaches. Further advances in the technologies will likely have the potential to extend these findings to multiple solid tumors and offer new hope to patients with limited options.”

Jerry McMahon, CEO of Cambridge, UK-based STORM Therapeutics, also noted the progress from AbelZeta but was less upbeat about CAR-Ts, pointing to the increased competition in the haematological cancers where they were first approved.

He said: “CAR-T therapies appear to have lost a little bit of their lustre, because of the lack of success in tackling solid tumour cancers, and because the field of haemotological cancers – where they have shown to be successful – is now so crowded.”

The KRAS-y gang

KRAS inhibitors first made a stir at ASCO around half a decade ago after drug makers struggled for years to find a way to exploit this common mutation, found in around 25% of all tumours.But since the first approval of Amgen’s first-in-class Lumakras (sotorasib), it’s not been plain sailing for this new drug class. After a first accelerated approval in KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer in 2021, Lumakras hit trouble with the FDA, which in December issued a Complete Response Letter rejecting an application for a full approval.Lumakras can stay on the market but will require a further additional confirmatory study to be completed no later than February 2028.Mirati Therapeutics, now part of Bristol-Myers Squibb’s rival Krazati (adagrasib) gained FDA accelerated approval in December 2022 in the same indication.A gang of other KRAS drugs reported data at ASCO, including Eli Lilly’s olomorasib, Genfleet’s fulzerasib, and InxMed’s garsorasib, all targeting the same mutation and indication.

Olomarasib is closest behind, with a Phase III trial ongoing in combination with Keytruda. Data reported at ASCO was from the Phase I/II LOXO-RAS-20001 study, which included 17 previously untreated patients. The combination regimen shrank tumours in 13 patients, giving an ORR of 77%, with median progression-free survival (PFS) not reached at the data cut-off point.

Genfleet’s fulzerasib has FDA clearance for a Phase III trial in an indication not yet served by a KRAS G12C inhibitor, as a second-line monotherapy for refractory metastatic colorectal cancer (CRC).

Small molecules, big impact

AstraZeneca’s Tagrisso (osimertinib) is a small molecule that has helped to turn around the Anglo-Swedish pharma’s fortunes over the past decade.And the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could have another string to its bow following data from the LAURA trial announced at ASCO.Already approved in a host of indications in non-small cell lung cancer (NSCLC), including as a first line treatment for EGFR-mutated disease, the FDA has accepted and granted Priority Review on the basis of the LAURA study in stage III epidermal EGFR-mutated NSCLC after chemoradiotherapy. If approved, Tagrisso will be indicated for EGFRm patients whose tumours have exon 19 deletions or exon 21 (L858R) mutations.In the trial, Tagrisso reduced the risk of disease progression or death by 84% compared to placebo and median progression-free survival (PFS) was 39.1 months in patients treated with Tagrisso versus 5.6 months for placebo.STORM’s Jerry McMahon said: “One of the most enthusiastically received presentations was AstraZeneca’s results of its kinase inhibitor Tagrisso, in patients with advanced EGFR-directed non-small cell lung cancer.”

Summarising findings from the small molecule research in NSCLC at ASCO, Michael Lahn, chief medical officer at iOnctura, said: “The findings from studies in KRAS G12C-mutated NSCLC, EGFR-mutated NSCLC and ALK-positive NSCLC show that small molecule oral drugs are likely to have a major role as therapies for different forms of this disease.”

AI at ASCO

The inexorable rise of artificial intelligence (AI) continued at ASCO, with some eye-catching work from nference, which presented a deep learning-enabled workflow designed to estimate real-world progression-free survival in metastatic breast cancer patients. This AI model uses natural language processing and structured EHR data to analyse clinical notes and radiology reports, achieving high sensitivity and accuracy. This innovation promises to enhance precision in tracking disease progression, potentially applicable to other cancer types as well.Qure.ai introduced an AI-powered “continuum” for lung cancer care, aimed at early detection and comprehensive management of the disease. This solution leverages AI to identify lung nodules from X-rays, measure their growth via CT scans, and monitor disease progression, thereby facilitating early intervention and improving patient outcomes.ASCO also showcased research where a novel AI model called PERCEPTION could accurately predict whether patients with cancer will respond to certain therapies.The research recently published in Nature Cancer indicated that single-cell RNA sequencing data may be used to help physicians more precisely match patients with the most effective drugs for their cancer type.Instead of current strategies relying on bulk sequencing of tumour DNA and RNA involving all cell types from a tumour, single-cell RNA sequencing provides higher resolution data from one cell alone.

Using widely available bulk RNA sequencing data and a machine learning technique to train an AI model, researchers were able to accurately predict how individual cells would respond to both cancer monotherapies and combination therapies.

ASCO 2024, which STORM’s Jerry McMahon wryly noted was attended by “only 45,000 people”, showed that “the science and technology around oncology continues to be very vigorous”.

The research showcased at ASCO will help inform clinical developments in other fields of medicine, he concluded.

“The many modalities being developed, the different forms, the variety of ways people conduct clinical trials – all this innovation affects other disease areas. Oncology has made gigantic progress, and that benefits other areas too.”