Originally published by our sister publication Specialty Pharmacy Continuum

By David Bronstein
The next two years may well see an explosion of FDA approvals for non-small cell lung cancer (NSCLC), with some of the drugs being first-in-class and/or best-in-class. If even a few of these agents make it through the regulatory gauntlet, clinicians will have a powerful new set of therapeutics to combat this challenging malignancy, a pharmaceutical industry analyst predicted at the NASP 2024 Annual Meeting & Expo, in Nashville, Tenn. 

The coming wave of NSCLC approvals was one of many oncology market trends that Ray Tancredi, RPh, MBA, CSP, the divisional vice president of Pharma Relations & Specialty Pharmacy Development at Walgreen Co., highlighted during his presentation. With the sheer numbers of NSCLC drugs that populated his slide deck, “I guess you can see a theme emerging here. And it’s an encouraging one,” Mr. Tancredi said, given the prevalence and severity of NSCLC.

Lung cancer is the second most common cancer in both men and women in the United States, with nearly 235,000 new cases projected to occur in 2024, he noted. NSCLC will account for up to 85% of those cases, with a five-year survival rate of only 28% (all stages combined).

Here are three of the more promising NSCLC agents Mr. Tancredi highlighted, with details on formulation, mechanism of action, safety and efficacy, and projected market entry. (Look for the November/December print issue of Specialty Pharmacy Continuum for a more complete roundup.)

Telisotuzumab Vedotin 

This IV product, marketed by AbbVie as Teliso-V, is a potential first-in-class anti-mesenchymal epithelial transition (c-Met) protein–directed antibody–drug conjugate that is designed to target c-Met overexpressing tumors, Mr. Tancredi noted. c-Met is a receptor tyrosine kinase that can be overexpressed in many solid tumors, including NSCLC.

Key safety and efficacy data on telisotuzumab vedotin were reported in the phase 2 LUMINOSITY trial (J Clin Oncol 2024;42[25]:3000-3011). A total of 176 patients with nonsquamous epidermal growth factor receptor (EGFR) wild-type NSCLC were included, with an eye toward determining how c-Met protein overexpression affected results. The overall response rate (ORR) was 28.6%. Patients with c-Met protein overexpression (defined as ≥25% tumor cells with 3+ staining) fared better, with an ORR of 34.6%.

The median overall survival was 14.5 months, with a slight nod to c-Met high expressors at 14.6%. Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%) and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%).

“It’s important to note that this trial included NSCLC patients with a c-Met expression who had failed at least two previous lines of chemotherapy,” Mr. Tancredi said. “There simply are no targeted therapies currently FDA approved for that indication.” 

On Sept. 27, AbbVie submitted a Biologics License Application (BLA) to the FDA for accelerated approval of telisotuzumab vedotin in adult patients with previously treated, locally advanced or metastatic EGFR wild-type, nonsquamous NSCLC with c-Met protein overexpression. The drug previously had been granted Breakthrough Therapy designation.

 “We may see Teliso-V reviewed and approved by the FDA  very soon—perhaps as early as this December,” Mr. Tancredi said.


Zipalertinib 

This oral therapy, developed by Taiho Pharmaceutical and Cullinan Therapeutics, was engineered to inhibit EGFR in patients with exon 20 insertion mutations, while sparing wild-type EGFR. In September, Cullinan Therapeutics announced safety and efficacy data from the pivotal phase 2b REZILIENT 1 study of 30 evaluable NSCLC patients with the exon 20 mutation. Patients were treated with zipalertinib after suboptimal responses to a median of three prior systemic anticancer regimens. The results, which were released at the European Society for Medical Oncology Congress 2024 (presentation 1245MO), in Barcelona, Spain, were as follows: One patient (3%) had a complete response, 11 patients (37%) had a partial response and 15 patients (50%) had stable disease. 

The most common treatment-related AEs in greater than 10% of patients (n=45) were rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%) and stomatitis (11%), the majority of which were grade 1/2. There were no grade 4/5 treatment-related AEs.

Antonio Passaro, MD, PhD, an oncologist at the European Institute of Oncology, in Milan, noted that in this challenging subset of NSCLC patients, zipalertinib has the potential for meeting “a significant emerging unmet medical need.” The drug “demonstrated promising efficacy, including a high overall response rate, and a manageable safety profile,” Dr. Passaro said in a company press release announcing the REZILIENT 1 data. 

“Zipalertinib is a unique formulation that’s distinct from other exon 20–directed agents, and not surprisingly, it has received a breakthrough therapy designation from the FDA,” Mr. Tancredi said. “We could see this reviewed and approved by the FDA  by the end of 2025.”

Datopotamab Deruxtecan 

This IV drug has a mechanism of action that may be a bit of a mouthful for those not up to speed on the latest metabolic underpinnings of cancer. It is an anti–tumor-associated calcium signal transducer (TROP)2 monoclonal antibody–topoisomerase I inhibitor conjugate. “AstraZeneca and Daiichi Sankyo entered in a global collaboration to jointly develop and commercialize this product last February,” Mr. Tancredi said. “The FDA accepted the manufacturers’ BLA, and some indications are that the FDA will review the drug in the near future.” (The Prescription Drug User Fee Act [PDUFA] date for datopotamab deruxtecan is scheduled for the first quarter of 2025, a company press release noted.)

If datopotamab deruxtecan does get approved, “it would be the first TROP2-directed antibody–drug conjugate for patients with lung cancer,” Mr. Tancredi said.

The BLA for datopotamab deruxtecan was based on the TROPION-Lung01 study (J Clin Oncol 2024 Sep 9. doi:10.1200/JCO-24-01544). The phase 3 trial compared the efficacy and safety of the investigational drug—referred to as dato-DXd in the study—versus docetaxel in patients with pretreated advanced/metastatic NSCLC. The most pronounced difference in efficacy was seen in a nonsquamous histology subgroup, where the median progression-free survival was 5.5 months in patients treated with dato-DXd versus 3.6 months in those given docetaxel (hazard ratio [HR], 0.63; 95% CI, 0.51-0.79). The median overall survival was 14.6 versus 12.3 months (HR, 0.84; 95% CI, 0.68-1.05).

As for safety, grade ≥3 treatment-related AEs occurred in 25.6% and 42.1% of patients in the dato-DXd and docetaxel groups, respectively.


The More, the Better

Mr. Tancredi acknowledged that it is difficult to predict when—or even if—these NSCLC cancer agents will be approved. But the data do look fairly strong, he noted. 

Assuming these drugs are reviewed favorably and then approved by the FDA, “remember that NSCLC is often diagnosed in advanced stages, making it all the more challenging to treat,” he said. “So the more chemotherapeutic agents we can add into the marketplace, the more likely we can achieve better responses for our patients.”

Mr. Tancredi reported no relevant financial disclosures.