NICE Recommends Entrectinib for ROS1+ Advanced NSCLC

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has recommended entrectinib (Rozlytrek) as a treatment option for ROS1-positive advanced non­–small cell lung cancer (NSCLC) in adults who have not received prior treatment with ROS1 inhibitors.¹

The committee concluded that entrectinib can be considered cost effective,” NICE stated in its final appraisal document. “Therefore, it can be recommended for routine commissioning as an option for treating ROS1-positive advanced NSCLC.”

The recommendation was supported by findings from a small study in which investigators did not compare entrectinib with anything else. The agent was examined in patients with previously treated disease and the available evidence suggested that it was effective in shrinking tumors and slowing disease progression.

To reach this decision, the appraisal committee reviewed evidence submitted by Roche, the manufacturer of the drug. Evidence was based on analyses from 53 patients with ROS1-positive advanced NSCLC from 2 phase 1 studies, ALKA-372-001 and STARTRK-1 (NCT02097810), as well as the phase 2 STARTRK-2 trial (NCT02568267).

STARTRK-2, is a single-arm, phase 2 basket trial in which entrectinib is being compared with pemetrexed (Alimta) and a platinum drug. A total of 207 patients with advanced or metastatic solid tumors and various gene alterations as well as 78 patients with ROS1-positive NSCLC were enrolled for assessment. The majority, or 73%, of patients had received prior therapy for advanced disease. All patients are given the licensed dose of entrectinib, which is 600 mg.

Data from the STARTRK-2 subgroup,² which had a May 2018 enrollment data cutoff date, were used in the appraisal. The company submitted updated analyses with a May 2019 enrollment data off, which confirmed the original data from the STARTRK-2 subgroup. “The results cannot be reported here because they are confidential,” the agency wrote in the final appraisal document. Roche’s pooled analyses from the ALKA, STARTRK-1 and STARTRK-2 trials were also updated and reported to the agency.

The efficacy-evaluable patient population for the pooled analyses included patients aged ≥18 years with locally advanced or metastatic ROS1 fusion–positive NSCLC who were given oral entrectinib at a dose of at least 600 mg once daily, with at least 12 months of follow up. All patients had an ECOG performance status ranging from 0 to 2. Patients who received prior treatment were permitted, with the exception of those who received prior ROS1 inhibitors. The primary end points of the analyses were the proportion of patients with an objective response and duration of response as assessed by blinded independent central review. The safety-evaluable patient population for the safety analysis included those with ROS1 fusion–positive disease enrolled in the 3 trials who had received at least 1 dose of entrectinib.

Patients were enrolled in the ALKA-372-001 trial from October 26, 2012 to March 27, 2018; participants were enrolled in the STARTRK-1 trial from August 7, 2014 to May 10, 2018; and enrollment for the STARTRK-2 trial began on November 19,2016 and is still ongoing. At a data cut-off of May 31, 2018, 77% (n = 41; 95% CI, 64-88) of 53 patients in the efficacy-evaluable population experienced an objective response. The median follow-up was 15.5 months, and the median duration of response reported with entrectinib was 24.6 months (95% CI, 11.4-34.8).

In the safety-evaluable population, 59% (n = 79) of 134 patients experienced grade 3 or 4 treatment-related adverse events (TRAEs). The most commonly reported events were weight increase (8%, n = 10) and neutropenia (4%, n = 5). Eleven percent (n = 15) of patients experienced serious TRAEs, with nervous system disorders (3%, n = 4) and cardiac disorders (2%, n = 3) among the most commonly reported toxicities. No treatment-related deaths were reported with the treatment.

Data from the integrated analysis of the 3 trials led to the FDA’s decision to grant the agent accelerated approval in August 2019 for the treatment of adults with ROS1-positive, metastatic NSCLC, as well as adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion.³

Results from the updated pooled analysis were considered in NICE’s decision. The survival data from the integrated analysis are still immature and not yet complete, and the results cannot be reported because they are confidential, according to the agency. However, the updated pooled analyses reported an overall response rate (ORR) of 73.4% (95% CI, 63.3-82.0) with entrectinib. Furthermore, the median progression-free survival (PFS) was 16.8 months (95% CI, 12.0-21.4) with entrectinib.

“The committee considered that the STARTRK-2 subgroup was representative of NHS clinical practice. It noted that only a small number of people with ROS1-positive NSCLC were included in the basket trial and that the results were immature,” the agency wrote. “However, the committee agreed that entrectinib produced a high ORR and slowed disease progression.”

In the STARTRK-2 patient subgroup, just under half (45%) of patients had brain metastases prior to study enrollment; 10% of patients had measurable lesions. Again, the results cannot be reported as they are confidential, but the pooled analyses with a minimum of 6 months of follow-up revealed an intracranial ORR of 79.2% (n = 19/24; 95% CI, 57.8-92.9) patients with measurable central nervous system (CNS) lesions at the start of the study. Based on these data, the committee agreed that the agent showed a high intracranial ORR in those with measurable CNS lesions.

In an effort to compare the effectiveness of entrectinib with pemetrexed, the company pulled data from patients with ALK-positive disease to serve as a proxy for those with ROS1-positive NSCLC. The rationale was that patients with ALK- and ROS1-positive disease are comparable in terms of demographics and clinical characteristics.

To this end, the company examined 2 studies to indirectly compare entrectinib with pemetrexed plus a platinum drug: the ASCEND-4 trial (NCT01828099), which examined ceritinib (Zykadia) versus pemetrexed and platinum in 375 patients with ALK-positive NSCLC, and the PROFILE 1014 trial (NCT01154140), which evaluated crizotinib (Xalkori) versus pemetrexed and platinum in 343 patients with ALK-positive disease.

In ASCEND-4, approximately 43% of patients received ceritinib after pemetrexed and platinum. Furthermore, the majority of patients, or 84%, received crizotinib after pemetrexed and platinum in the PROFILE 1014 trial.

“The committee was concerned about using proxy data, however in this instance the Evidence Review Group (ERG) and clinical experts agreed that this was acceptable because no ROS1-positive evidence was available,” the agency noted. “However, the committee highlighted the uncertainty the proxy data introduced to the estimated results. The committee agreed to explore the proxy data in its decision making. However, it considered the estimates from the indirect comparison to be uncertain.”

The estimated mean overall survival with pemetrexed and platinum was 39.2 months using the ERG’s approach and 15.6 months using the company’s approach. Clinical experts considered the ERG’s approach to be an overestimation with regard to survival benefit with pemetrexed plus platinum and the company’s approach to be an underestimation. Experts also noted that the post-progression survival gain with entrectinib when utilizing the company’s approach was “implausibly high.”

In sum, the experts agreed that, most likely, the true survival benefit falls somewhere between the 2 approaches utilized. “The committee agreed with the clinical experts and decided to consider both approaches in its decision making,” the agency wrote in the final appraisal document.

The company, ERG, and clinical experts all agreed that the life expectancy of patients who had received treatment with pemetrexed plus platinum was less than 24 months. They also agreed that entrectinib could extend life by more than 3 months compared with pemetrexed plus platinum. As such, entrectinib was considered to be a life-extending, end-of-life treatment versus pemetrexed and platinum, meeting both of NICE's criteria.

With regard to cost-effectiveness, estimates were found to be within an acceptable range with regard to the use of National Health Service (NHS) resources for end-of-life treatments. Specifically, the incremental cost-effectiveness ratio (ICER) for entrectinib was in the range of £37,910 compared with £42,475 with pemetrexed plus platinum per quality-adjusted life year (QALY) gained.

Furthermore, the company’s preferred base-cost post-technical engagement ICER ranged from £21,607 to £23,457 per QALY gained.

Although the data were immature, the committee was persuaded that the highest ICER for entrectinib versus pemetrexed plus platinum was still likely to be below £50,000 per QALY gained.

“The committee concluded that entrectinib can be considered cost effective,” the agency wrote in the document. “Therefore, it can be recommended for routine commissioning as an option for treating ROS1-positive advanced NSCLC.”

References

1. Final appraisal document: entrectinib for treating ROS1-positive advanced non-small-cell lung cancer. National Institute for Health and Care Excellence. June 2020. Accessed June 15, 2020. bit.ly/2Y4MZdN
2. Drilon A, Siena S, Dziadziuszko R, et al. Entrectinib in ROS1 fusion–positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):261-270. doi:10.1016/S1470-2045(19)30690-4
3. FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor. News release. FDA. August 15, 2019. Accessed June 15, 2020. https://bit.ly/2TDORX1