Cutting-Edge Targeted, Cytotoxic, and Immunologic Therapies Form Next Generation of mNSCLC Treatments

At the 2024 World Conference on Lung Cancer, Brian S Henick, MD, Columbia University, spoke about next-generation solutions in treating non-small cell lung cancer (NSCLC), highlighting several abstracts presented throughout the weekend that showcase the potential of new treatments and therapies.¹

NSCLC mutations necessitate new forms of treatment. Image credit: © cunaplus | stock.adobe.com

To begin, the results demonstrating volrustomig and platinum doublet chemotherapy’s (CTx) effect in first-line NSCLC were highlighted. Volrustomig, a novel PD-1/CTLA-4 bispecific antibody, is designed to fully inhibit PD-1 while purposely blocking CTLA-4 on activated T-cells.²

With the coadministration of PD-(L)1 and CTLA-4 blockade, greater T cell proliferation has been observed. Additionally, volrustomig and has shown promising efficacy in advanced NSCLC, especially in those patients with PD-L1 T-cells of <1%. These patients represent a gap in care, with the addition of anti-CTLA-4 into the treatment landscape providing an alternative for increased efficacy.¹

Patients in this trial were separated into nonsquamous (n = 120) and squamous (n = 20) cohorts, each receiving volrustomig at 750 mg intravenously along with CTx. The primary end points were overall response rate (ORR) for the nonsquamous arm and safety for the squamous arm, while key secondary end points were safety, duration of response, disease control rate (DCR), and progression-free survival (PFS).¹

In an important development, almost all the patients in the trial had some type of treatment-related adverse event (TRAE), with a third of patients having a severe TRAE that required discontinuation of volrustomig. Two deaths were attributed to volrustomig, due to pneumonitis and hypophysitis; 4 were related to CTx, while 1 death was related to the volrustomig and CTx combination.1

Regarding efficacy, the ORR in the nonsquamous cohort was 43.7% while the DCR was 84.9%. In the squamous arm, ORR was 65.0% and DCR was 95.0%. Across all patients, regardless of histology, a majority (~85-95%) achieved disease control.¹

Based on these results, Henick posed the question of whether bispecifics such as volrustomig can compete with the tried and trusted method of using anti-PD-(L)1 monoclonal antibodies. Henick referenced the HARMONi-2 trial (NCT05899608), which compared ivonescimab, a bispecific, with pembrolizumab; ivonescimab led to meaningful improvement in PFS with both low and high PD-(L)1, irrespective of squamous or nonsquamous status.¹

Next, a study examining the effects of divarasib as a single-agent treatment and it in combination with atezolizumab in patients with KRAS G12C-positive NSCLC was shown. Divarasib is thought to be one of the most potent KRAS off-inhibitors agents currently under investigation, according to Henick.³

The first part of the study evaluated patients with advanced or metastatic tumors with KRAS G12C mutation who received single agent divarasib. Investigators evaluated safety, pharmacokinetics, and preliminary antitumor activity that was associated with divarasib. In patients receiving a 400 mg dose (n = 44), ORR was 59.1%, median DOR was 14.0 months (95% CI: 11.1, 34.9), and median PFS was 15.3 months (95% CI: 12.3, 26.1).¹

Common TRAEs reported were nausea, diarrhea, and vomiting; most were grade 1 TRAEs, and occurred early in the trial. In the 31 patients who continued divarasib as a single-agent treatment beyond 1 year, 17 (54.8%) experienced a new-onset TRAE after one year. In a key result, no new-onset TRAEs led to any dose reductions or withdrawal of divarasib.¹

Referencing a chart from Caicun Zhou, PhD, MD’s presentation earlier in the conference, divarasib, when compared to other single agent KRAS G12C inhibitors in the second-line NSCLC setting, performs better in terms of ORR, median PFS, and median DOR. This comparison highlights divarasib’s potential as it continues through clinical trials.¹

Divarasib was then evaluated in combination with atezolizumab in the same population. Divarasib was given in either 200 mg (n = 18) or 400 mg (n = 21), and the safety profile was similar between the 2 groups. Most of the patients experienced at least one TRAE, but only 28% experienced a grade 3 to 5 TRAE. TRAEs were determined to be consistent between single agent divarasib and atezolizumab safety profiles.¹

Among patients who hadn’t received any KRAS G12C inhibitors prior to the study (n = 13), ORR was 61.5% while it was 55.6% (n = 27) in the overall population. When compared to some of the other KRAS G12C inhibitor and immunotherapy combination, divarasib and atezolizumab ranked highly, but still below other combinations in terms of ORR.¹

Based on these highlighted trials, Henick discussed some key takeaways. Regarding cytotoxics and antibody-drug conjugates, the next step should be identifying patients most likely to benefit from treatment, using patient histology, novel biomarkers, and applying them to direct care. Furthermore, if bispecific antibodies are the next generation of NSCLC treatment, treatment providers must determine which patients are most likely to benefit.¹

Lastly, the landscape for KRAS G12C inhibitors is clearly competitive, and Henick recommends the implementation of an optimized therapeutic window for monotherapies and combination partners to fully flesh out the safety and efficacy of these treatments.¹

REFERENCES

1. Henick B. Next-gen solutions in mNSCLC: Breakthroughs in cytotoxic therapy and ADC, latest advances in mNSCLC immunotherapy, cutting-edge targeted therapies. 2024 World Conference on Lung Cancer, San Diego, California. Presented September 10, 2024. Accessed online September 11, 2024.

2. ClinicalTrials.gov. A study to evaluate MEDI5752 in subjects with advanced solid tumors. National Library of Medicine. Last updated June 24, 2024. Accessed September 11, 2024. https://clinicaltrials.gov/study/NCT03530397

3. ClinicalTrials.gov. A study to evaluate the safety, pharmacokinetics, and activity of GDC-6036 alone or in combination in participants with advanced or metastatic solid tumors with a KRAS G12C mutation. National Library of Medicine. Last updated September 5, 2024. Accessed September 11, 2024. https://clinicaltrials.gov/study/NCT04449874