As physicians, researchers and pulmonary oncology specialists make their way to Barcelona for the IASLC 2025 World Conference on Lung Cancer (WCLC), many are waiting with bated breath for trial readouts that could alter the treatment paradigm and improve therapeutic options for patients with lung cancer.

During the three-day conference, there will be a strong focus on non-small cell lung cancer (NSCLC), which constitutes approximately 85% of all lung cancer cases. Despite the widespread availability of treatment options for patients with this indication, the average five-year survival rate for the disease is 32% - highlighting the need for effective treatments at all stages of the disease.

Targeted therapies are now at the forefront of the NSCLC treatment revolution, with blockbuster oncology drugs like Merck’s Keytruda (pembrolizumab) offering survival benefits previously unseen in the indication.

Meanwhile, several candidates are being explored in Phase III trials, including tyrosine kinase inhibitors (TKIs), bispecific & monoclonal antibodies (mAbs) and ataxia telangiectasia and Rad3-related (ATR) kinase inhibitors.

Bayer’s TKI for HER-2 mutated disease

Bayer is currently exploring the potential of its TKI sevabertinib, or BAY 2927088, in the Phase III SOHO-02 trial (NCT06452277). During the study, the drug will be compared to standard of care (SoC) chemotherapy in patients with advanced NSCLC – specifically those who have human epidermal growth factor receptor 2 (HER2) mutations. The study is set for primary completion in 2027.

Though it is still recruiting participants, the five-year trial aims to enrol 278 patients across 36 countries, who will be randomised to receive sevabertinib twice daily through oral administration or standard treatment in 21-day cycles via intravenous infusion. The primary endpoint of this study is progression-free survival (PFS), while key secondary endpoints measure overall survival (OS) and objective response rates (ORR).

Dr. Balasz Halmos, thoracic oncologist at the Albert Einstein College of Medicine and Montefiore Medical Centre, notes that the drug exhibited “excellent early data” in its Phase II trial in HER2+ NSCLC, characterised by high response rates, fair durability of activity and a reasonable toxicity profile.

However, following the approval of Boehringer Ingelheim’s Hernexeos (zongertinib) in August 2025, Halmos states: “While it will be nice to have options when prescribing a TKI, it will be hard to separate the two in terms of efficacy and safety”.

Dr. Roy Herbst, chief of medical oncology at Yale New Haven Hospital, also sees great potential in sevabertinib, having tried to obtain the drug for a patient of his in upstate New York. “The results are phenomenal, both in treated and pretreated patients,” he says.

“We could prescribe sevabertinib in the first-line setting, where response rates are extremely high, or in the second-line setting, where it also shows strong activity. It would likely be best to combine it with chemotherapy, especially after the positive results of the FLAURA-2 trial looking at Tagrisso plus chemotherapy,” Herbst adds.

Tagrisso (osimertinib) is an FDA-approved, epidermal growth factor receptor (EGFR)-targeting TKI suitable for first-line treatment of metastatic NSCLC with most common EGFR mutations. It demonstrates a similar mechanism of action to sevabertinib, which inhibits both EGFR and HER2.

“Though Bayer will need to conduct other confirmatory trials, this is a great advance in the NSCLC field with immediate impact,” Herbst remarks.

Biswajit Podder, PhD, oncology and haematology analyst for GlobalData, echoed this sentiment, but clarified that the drug could only redefine first-line practice “if its PFS, OS and tolerability profile prove better than platinum doublet chemotherapy and current TKIs available on the market”.

AstraZeneca trying to overcome ATR inhibitor difficulties

Meanwhile, AstraZeneca has hedged its bets on ATR as a target, which has, so far, been unsuccessful as a target in NSCLC. The UK-based pharma is conducting the Phase III LATIFY study (NCT05450692), exploring how a combination of its ATR kinase inhibitor and blockbuster mAb Imfinzi (durvalumab) compares with docetaxel.

During the study, 594 patients across 192 locations who are refractory to treatment with anti-PDL1s and platinum-based chemotherapy will be randomised to receive either oral ceralasertib plus intravenous Imfinzi or intravenous docetaxel. The primary endpoint is OS, while secondary endpoints will measure PFS and objective response rates (ORR).

Dr. Åslaug Helland, Research Director at the OECI-accredited Oslo Comprehensive Cancer Centre, was cautiously sceptical about ATR’s role as a target. “Pharma and biotech companies have been trying to develop ATR and Ataxia-telangiectasia mutated, symbol (ATM) inhibitors for some years, though none have made it to market,” she says.

“So far, the patient cohort for the Phase III study has experienced a lot of toxicity – specifically anaemia, nausea and fatigue. However, I think ATR inhibitors like ceralasertib could hold potential when combined with radiotherapy, immunotherapy or chemotherapy – though more evidence is required to prove this,” says Helland.

Meanwhile, Podder believes: “A positive OS result would establish a practical option after chemotherapy and immunotherapy, while a negative outcome would likely narrow ATR’s role to biomarker-selected subsets.” However, he adds that the Phase III trial design could raise concerns, as it “fails to explore ceralasertib and Imfinzi as monotherapies, which limits attribution of benefit to ATR inhibition – complicating cross-trial comparisons”.

BioNTech’s anti-CTLA-4 mAb toxicity a concern

After purchasing the exclusive global rights to anti-CTLA-4 mAb gotistobart – previously known as ONC-392 – from OncoC4 in March 2023, BioNTech has worked with the Maryland-based company to carry out the Phase III PRESERVE-003 trial (NCT05671510), which is comparing the drug’s efficacy as a monotherapy to docetaxel.

The study has enrolled 600 patients across 160 locations – all of whom have progressed on PD-1 or PD-L1 inhibitors. Patients will be randomised to receive intravenous gotistobart at a low dose (3mg/kg), high dose (6mg/kg) or docetaxel every 21 days. It is set for primary completion in June 2026.

Though Herbst sees promise in CTLA-4 as a target in NSCLC, he cautions that the drug’s toxicity profile may overshadow its efficacy. “There have been a few different ways of targeting CTLA-4 that have shown some activity – especially in PDL-1-low or cold tumours – but at what price?”

“To utilise CTLA-4, we will have to find a less toxic way,” Herbst concludes.

Halmos echoes this sentiment: “The issue with anti-CLTA-4 drugs is their toxicity, but the lack of efficacy issue is also something to consider. There are some signals of added activity for patients with low tumour proportion score (TPS), as well as those with serine/threonine kinase 11 (STK-11) or Kelch-like ECH-associated protein 1 (KEAP-1), but these have to be borne out in larger clinical trials,” he comments.

Meanwhile, Helland says she is “not too concerned” about gotistobart’s toxicity, as physicians are already familiar with the tolerability profiles of both Yervoy (cepilimab) and Imjudo (tremelimumab). She considers the side effect profile of both drugs “manageable when acknowledged and treated accordingly”.

“If proven effective, anti-CTLA-4 drugs could fulfil the unmet need in patients who have progressed on standard immunotherapy and chemotherapy, as we don’t really have anything good to treat patients with after that point,” Helland concludes.