Toxicity Considerations Drive Treatment Strategies in the New Era of NSCLC Therapy

As treatment options for patients with non–small cell lung cancer (NSCLC) have expanded to encompass immunotherapies and new antibody-drug conjugates (ADCs) such as telisotuzumab vedotin-tllv (Emrelis) and datopotamab deruxtecan-dlnk (dato-DXd; Datroway), safety considerations have become a key part of the treatment selection and sequencing process due to the risk of severe autoimmune toxicities, according to Balazs Halmos, MD, MS, and Jamie E. Chaft, MD.

“It’s nice to extend lives, but we want to maintain those lives at the highest quality possible,” Halmos said in an interview with OncologyLive. “We’re learning a lot about the novel AEs of immunotherapies, targeted therapies, ADCs, and bispecific T-cell engagers.”

Halmos is the associate director of clinical science and a professor in the departments of Oncology (Medical Oncology) and Medicine (Oncology and Hematology) at Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York.

Chaft is a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

How do toxicity considerations drive frontline immunotherapy selection?

Safety considerations are a key factor in determining which patients are good fits for a combination immuno-oncology (IO) or a single-agent IO approach as both pembrolizumab (Keytruda) monotherapy and the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) are indicated for patients with untreated NSCLC, according to Chaft. “We need to consider [which patients have] appropriately aggressive disease to justify the added risk of CTLA-4 inhibition and the associated immune-related adverse effects [irAEs],” she commented in an interview with OncologyLive.

Following the May 2020 FDA approval of nivolumab plus ipilimumab in the frontline setting, new safety considerations are needed to determine which patients are proper candidates for the addition of the CTLA-4 inhibitor ipilimumab to the traditional PD-1–targeted approach.1 Findings from the phase 3 CheckMate 227 trial (NCT02477826), which supported the approval, showed that immune-mediated pneumonitis occurred in 9% (n = 50/576) of patients.2 Grade 2 (4.0%), 3 (3.5%), and 4 (0.5%) instances of the irAE were all reported, and 4 patients experienced fatal cases.

“[Using these agents] requires a lot of education for us, our team, and the patients to be able to monitor these AEs and intervene in the right ways,” Halmos said. “[These include] stopping immunotherapy, introducing steroids, and sometimes building upon the steroid management plan with additional agents, depending on the severity and extent of the toxicity.”

How should oncologists approach identifying the right patients for the new ADCs in NSCLC?

Following the 2025 FDA approvals of the ADCs telisotuzumab vedotin and dato-DXd for biomarker-selected populations of patients with NSCLC, treatment safety considerations play a crucial role in determining which patients are good candidates for these agents due to their unique toxicity profiles, Halmos said.3,4

“These agents provide additional efficacy but also [come with] new challenges in terms of adverse effects [AEs]. For example, a unique AE with telisotuzumab vedotin is neuropathy. We need to watch out for this and manage it appropriately.”

Safety findings from the phase 2 LUMINOSITY trial (NCT03539536), which supported the FDA approval of telisotuzumab vedotin, revealed that any-grade peripheral neuropathy occurred at a rate of 51% in the safety population (n = 168); 11% of these instances were grade 3 or 4 in severity.3 The median time to onset of peripheral neuropathy was 105 days (range, 1-472) and 13% of patients were forced to permanently discontinue therapy due to this AE.

Moreover, data from an analysis of LUMINOSITY, which examined the safety and efficacy of telisotuzumab vedotin in relation to prior therapy, showed that the safety profile of the agent was generally consistent among patients who received prior platinum-based therapy (n = 164), immune checkpoint inhibitors (ICIs; n = 135), or platinum-based therapy plus an ICI (n = 132).5 Any-grade peripheral sensory neuropathy was reported at similar rates across the subgroups (32% vs 33% vs 34%). Patients who received prior platinum-based therapy were at a slightly lower risk of experiencing any-grade peripheral edema (16%) compared with those who received a prior ICI (20%) or prior platinum- based therapy plus an ICI (20%).

The label for telisotuzumab vedotin also includes a warning for interstitial lung disease (ILD)/pneumonitis.3 In LUMINOSITY, any-grade ILD/pneumonitis occurred in 10% of patients who received telisotuzumab vedotin; grade 3 and 4 cases were reported at respective rates of 3% and 0.6% and 3 patients died due to the AE. The median time to onset of ILD/pneumonitis was 48 days (range, 23-85) and 7% of patients were forced to permanently discontinue treatment due to ILD/pneumonitis.

“We’re getting more accustomed to [managing] the on-target AEs of the MET[-directed agents],” Chaft noted. “Understanding when visual change and coughing need to be respected are key in the sense of preventing progressive toxicity by holding therapy and [performing] further investigation.”

ILD/pneumonitis is also a safety concern among patients treated with dato-DXd, although it occurred slightly less frequently compared with patients who received telisotuzumab vedotin. Findings from a pooled analysis of the phase 3 TROPION-Lung01 (NCT04656652), phase 2 TROPION-Lung05 (NCT04484142), and phase 1 TROPION-PanTumor01 (NCT03401385) studies showed that patients who received dato-DXd (n = 484) experienced any-grade ILD/ pneumonitis at a rate of 7%, including grade 3 and 4 instances at respective rates of 0.6% and 0.4%. Fatal cases of ILD/pneumonitis occurred at a rate of 1.7%.6

In a paper published in the Oncologist, Lisberg et al recommended that patients with NSCLC who are receiving dato-DXd should be monitored for ILD/pneumonitis via a contrast-enhanced chest CT scan every 6 weeks and oxygen saturation assessments.6 Treatment with the agent should be withheld immediately if ILD/ pneumonitis is suspected, regardless of the grade. The study authors also noted that blood cultures and complete blood count, bronchoscopy and bronchoalveolar lavage, pulmonary function tests, pulse oximetry, arterial blood gas testing, and infectious disease consultation can also be considered, if indicated.

Where can I learn more about treatment selection considerations?

At the upcoming 20th Annual New York Lung Cancers Symposium®, which will take place on November 15, 2025, in New York, New York, investigators will gather to further discuss how toxicity considerations should inform treatment decision-making and sequencing for patients with NSCLC in multiple clinical scenarios.7 During the event, which will be cochaired by Halmos and Chaft, experts will also present the latest data on immunotherapy and targeted approaches for the treatment of patients with metastatic disease, participate in multidisciplinary discussions covering clinical questions and challenges, and highlight the evolving landscape of biomarker testing.

“I’m most excited for the educational value of the drastic changes we’ve seen in small cell lung cancer; we will learn about both the efficacy of our new agents as well as how to manage a unique profile of AEs,” Chaft said. “I’m also [looking forward] to hearing Alexander E. Drilon, MD, and Joshua K. Sabari, MD, help us navigate which tyrosine kinase inhibitor to pick for uncommon oncogene-driven lung cancers and how to manage their AE profiles.”

“Friendly [discussion] can ultimately solve cases and problems that we face. [This meeting] has a practical focus. It’s not just rehashing data; it’s [grounded in] how the data apply to your clinic and patients. That practical edge makes [this meeting] useful for the day-to-day practice of the community practitioner,” Halmos added.

References

1. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). FDA. May 15, 2020. Accessed August 27, 2025. bit.ly/4pVGZiw
2. Yervoy. Prescribing information. Bristol-Myers Squibb; 2020. Accessed August 27, 2025. bit.ly/4gRrKTn
3. Emrelis. Prescribing information. AbbVie; 2025. Accessed August 27, 2025. bit.ly/4nV8h6Bf
4. Datroway. Prescribing information. Daiichi Sankyo; 2025. Accessed August 27, 2025. bit.ly/4nzJO7lf
5. Goldman JW, Lu S, Bar J, et al. LUMINOSITY, a phase 2 study of telisotuzumab vedotin in patients with c-Met protein– overexpressing non-squamous EGFR-wildtype advanced NSCLC: efficacy outcomes by prior therapy. J Clin Oncol. 2025;43(suppl 16):8618. doi:10.1200/JCO.2025.43.16_suppl.8618
6. Lisberg A, Huppert LA, Halmos B, Ledezma B, Soto-Romano V, Traina TA. Datopotamab deruxtecan-associated select adverse events: clinical practices and institutional protocols on prophylaxis, monitoring, and management. Oncologist. Published online July 23, 2025. doi:10.1093/oncolo/oyaf225 7. 20th Annual New York Lung Cancers Symposium. Physicians’ Education Resource LLC. Accessed August 27, 2025. bit.ly/3VjMObh