ICON supported a randomised Phase 3 study to examine the study drug in combination with nivolumab vs chemotherapy in patients with checkpoint inhibitor refractory non squamous NSCLC. The original protocol developed by the sponsor deviated from the global non-small cell lung cancer (NSCLC) standard of care (SOC), which limited the number of participating countries and led to low enrollment. ICON worked with the sponsor to leverage our data intelligence and amend the protocol to align inclusion/exclusion criteria to the global SOC treatment patterns, resulting in a higher enrollment rate and a more extensive country selection.

The sponsor’s protocol sought registrational approval for adding the investigational product (IP) to nivolumab in a second-line (2L) setting.

The sponsor’s original protocol design stipulated that:

• Only 2L patients were eligible
• The first-line (1L) regimen was an immuno-oncology (IO) platinum triplet/quadruplet
• Patients were randomised to IP plus IO vs docetaxel alone

The original protocol was not aligned with the global SOC on multiple levels, which resulted in low enrollment and a limited country mix.

ICON determined this sponsor’s study was the only global study restricting 1L patient eligibility to an IO platinum triplet/quadruplet regimen. Analysis of 28 competing global trials demonstrated that all were allowing 1L to be either IO platinum triplet/quadruplet or platinum + chemo doublet followed by IO post-progression.

Figure 1 shows 65% of 1L patients are treated with IO regimens, and 51% of those patients are treated with an IO platinum triplet, resulting in a 33% eligibility rate for 1L patients. While IO platinum triplet regimens are prevalent in the US, many patients were excluded due to the limitation to only 2L patients post-1L triplet/quadruplet treatment. Countries outside of the US often lack triplet-regimen reimbursement despite approval, which severely limited the country selection. The SOC ex-US remains 1L platinum based chemotherapy followed by monotherapy checkpoint inhibitor treatment.

Furthermore, the protocol expected oncologists to treat 2L patients with docetaxel as the SOC comparator arm. Figure 2 shows 17% of 2L patients are treated with single agent chemotherapy, and only 31% of those patients are treated with docetaxel, resulting in a 5% acceptability rate for 2L patients. This suggests the SOC for 2L patients is not docetaxel but an IO-containing regimen (57% of patients). Use of single-agent treatment with docetaxel is more prevalent in 3L patients; a SOC comparator arm permitting 3L patients would be more acceptable than with 2L patients alone.

Due to the protocol restrictions for 1L patients and the misalignment to the typical SOC, the study experienced low enrollment and a restricted country mix.

With this analysis of ICON’s data intelligence assessing patterns by treatment line, combined with our therapeutic expertise and local country SOC knowledge, ICON presented a data-driven rationale for the enrollment challenges the sponsor was facing.

ICON worked with the sponsor to amend the protocol to align the inclusion/exclusion criteria with treatment patterns and the usual SOC, which enabled:

• 1L patients on a platinum-based chemotherapy doublet regimen followed by IO post progression (as well as continuing to allow 1L IO platinum triplet/quadruplet)
• 2L or 3L patients to be included to better align with docetaxel monotherapy in the comparator arm

This produced a greater number of eligible patients, higher enrollment, and a more viable country mix. It proved crucially important to leverage data intelligence and collaborate early during protocol development to ensure feasible enrollment and study success.