Cancer vaccine for advanced NSCLC beats chemo on survival, safety in phase III trial

T-cell vaccination with OSE2101 prolongs overall survival (OS) and is associated with fewer adverse events (AEs) compared with chemotherapy in select patients with HLA-A2-positive advanced nonsmall cell lung carcinoma (NSCLC), according to the results of the phase III ATALANTE-1 trial.

While data from 219 patients (median age 65 years, 74 percent men) showed no significant difference in the primary endpoint of OS between those who received OSE2101 (n=139) and those who received standard-of-care (SoC) chemotherapy (n=80; 8.8 vs 8.3 months; hazard ratio [HR], 0.86, 95 percent confidence interval [CI], 0.62–1.19; p=0.36), a positive signal for OS was seen with OSE2101 in the subgroup of patients who showed secondary resistance to immune checkpoint blocker (ICB; n=118).

The median OS in the subgroup was longer by 3.6 months with OSE2101 than with SoC (11.1 vs 7.5 months; hazard ratio [HR], 0.59, 95 percent CI, 0.38–0.91; p=0.017). The 12-month OS rates were 44.4 percent in the OSE2101 arm and 27.5 percent in the SoC arm. [Ann Oncol 2023;doi:10.1016/j.annonc.2023.07.006]

Aside from improving OS, OSE2101 also increased postprogression survival (7.7 vs 4.6 months; HR, 0.46, 95 percent CI, 0.27–0.79; p=0.004), delayed worsening of Eastern Cooperative Oncology Group (ECOG) performance status (9.0 vs 3.3 months; HR, 0.43, 95 percent CI, 0.23–0.80; p=0.006), and maintained quality of life as assessed by the global health status and physical and role functions (p=0.045).

As for safety, grade 3 AEs occurred in 35.4 percent of patients in the OSE2101 arm and in 64.9 percent in the SoC arm (p=0.002), with the AEs being treatment-related in 11.4 percent and 35.1 percent (p=0.003), respectively. The most common severe drug-related AEs were grade 3 pyrexia with OSE2101 (2.5 percent) and grade 3-4 neutropenia and asthenia with SoC (16.2 percent each).

There were no fatal AEs in either treatment arm and no grade 4 AEs in the OSE2101 arm. AEs led to treatment discontinuation for two OSE2101-treated patients (2.5 percent) and in four docetaxel-treated patients (10.8 percent), but none of which were related to treatment. Of note, the safety profile in the overall population was consistent with that in the subgroup of patients with secondary resistance to ICB.

These data support that chemotherapy-sparing strategies are feasible and safe in the treatment of advanced NSCLC population with secondary resistance to immunotherapy, according to investigators led by Prof Benjamin Besse, Director of Clinical Research at Gustave Roussy Institute in Villejuif, France.

“OSE2101 is the first cancer vaccine to demonstrate positive results on survival in a randomized phase III trial in advanced and metastatic NSCLC cancer patients in third line. A significant reduction of the risk of death by 41 percent was achieved with a better safety profile and a maintained quality of life,” Besse said in a statement.

“Further evaluation is clearly warranted in a second line of treatment … to potentially make this cancer vaccine available to hard-to-treat patients in failure and with high medical needs,” he added.

In the overall ATALANTE-1 population, one-third of patients had squamous NSCLC and 9 percent had never used tobacco. Nineteen percent of patients presented with three metastatic sites, with 16 percent and 19 percent having brain and/or liver metastases, respectively. Prior ICB treatment lasted between 12 and 24 weeks in 42 percent of patients and >24 weeks in 58 percent of patients.

In the SoC arm, 81 percent of patients received docetaxel (75 mg/m² intravenously over 1 hour) and 19 percent received pemetrexed (500 mg/m² intravenously over 10 minutes), with both drugs given every 3 weeks with premedication, according to international guidelines. In the OSE2101 arm, patients received the drug at 5 mg on day 1 every 3 weeks for six cycles, then every 8 weeks until 1 year of treatment and every 12 weeks thereafter. The median duration of treatment was 63 days, and the median number of doses was 4.0 in the two treatment arms.

Secondary resistance

Besse highlighted primary resistance and secondary resistance as the main barriers to improving outcomes in advanced NSCLC. Primary resistance is defined as the inability to respond following initial drug exposure. Sometimes, patients show objective response or achieve prolonged stable disease (>6 months), and then experience disease progression in the setting of ongoing treatment. This is characterized as secondary resistance. Secondary resistance to ICB in ATALANTE-1 was defined as progression occurring ≥12 weeks after sequential treatment with chemotherapy and ICB. [J Clin Oncol 2022;40:598-610; Cancer Cell 2020;37:443-455; J Immunother Cancer 2020;8e000398]

“Biologically, secondary resistance to ICB may occur through alterations in antigen presentation, and more frequently by T-cell exhaustion leading to progressive loss of effector function measured by IFN-g production, whereby exhausted cytotoxic CD8þ T-cells fail to control late-stage tumour progression,” Besse noted. [Front Immunol 2020;11:622509]

“The mechanism of action of OSE2101 that enhances a new specific CD8þ T-cell effector function, and which maintains antigen presentation and avoids immune escape leading to decreased T-cell recognition of the tumour, is a mechanistically plausible explanation of the clinical benefit observed in our study and in emerging new studies with cancer vaccines,” he added. [J Clin Oncol 2023;41:373-384]

*Quality of Life Questionnaire Core 30