Sintilimab Regimen Improves PFS in Frontline Squamous NSCLC

Caicun Zhou, MD, PhD

Adding the PD-1 inhibitor sintilimab injection (Tyvyt) to gemcitabine (Gemzar) and platinum-based chemotherapy improved progression-free survival (PFS) as a frontline treatment in patients with advanced or metastatic squamous non—small cell lung cancer (NSCLC), meeting the primary end point of the phase 3 Chinese ORIENT-12 trial.¹

"Lung cancer is the leading cause of cancer death (25.2%), of which NSCLC accounts for 80% to 85%, with about 35% of those patients having the squamous subtype. In the past 20 years, drug development to treat NSCLC has been mainly focused on nonsquamous NSCLC, while drug development of squamous NSCLC has been slower due to its lack of driving mutation and its unique epidemiological, histopathological and molecular characteristics," Caicun Zhou, MD, PhD, head of the Department of Oncology, Shanghai Pulmonary Hospital, stated in the press release.

"The emergence of the anti-PD-1 antibody has brought a new treatment modality for patients with squamous NSCLC. We are delighted to see that Tyvyt in combination with gemcitabine and platinum chemotherapy has met the predefined primary end point in the ORIENT-12 study. Different from the KEYNOTE-407 study in a different chemotherapy regimen, ORIENT-12 has demonstrated for the first time significant PFS benefit with a PD-1 inhibitor in combination with gemcitabine and platinum in first-line squamous NSCLC," added Zhou.

The phase 3, double-blind ORIENT-12 trial (NCT03629925) included 357 patients with locally advanced or metastatic squamous NSCLC. Patients were randomized in a 1:1 ratio to first-line treatment with sintilimab at 200 mg or placebo combined with gemcitabine for injection and platinum-based chemotherapy. Treatment was administered every 3 weeks for 4 to 6 cycles, followed by maintenance therapy with sintilimab or placebo. Patients received therapy until disease progression or unacceptable toxicity. The study design allowed for conditional crossover. Beyond the primary PFS end point, secondary end points included overall survival (OS) and safety.

Previously, the National Medical Products Administration (NMPA) of China accepted a supplemental New Drug Application (sNDA) for the PD-1 inhibitor sintilimab injection for use in combination with pemetrexed (Alimta) and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous NSCLC.²

The sNDA is based on findings from the phase 3 ORIENT-11 trial (NCT03607539), in which the sintilimab regimen significantly improved the median PFS versus pemetrexed and platinum alone in patients with advanced or recurrent nonsquamous NSCLC without EGFR mutations or ALK rearrangements. At a median follow-up of 8.9 months, the median PFS, per independent review, was 8.9 months versus 5 months, respectively (HR, 0.482; 95% CI, 0.362-0.643; P <.00001). No new safety signals with sintilimab emerged compared with prior research. The full study details will be presented at a future medical meeting.

In the double-blind, randomized phase III ORIENT-11 trial, researchers evaluated the efficacy and safety of sintilimab injection or placebo in combination with pemetrexed and platinum-based therapy as a first-line treatment for patients with advanced or recurrent nonsquamous NSCLC without sensitive EGFR mutations or ALK rearrangements. The injection is given at 200 mg along with 4 cycles of pemetrexed/platinum-based therapy, followed by 200 mg of sintilimab injection and pemetrexed maintenance.

To be eligible for enrollment, patients with advanced nonsquamous NSCLC had a life expectancy ≥3 months, ≥1 measurable lesion, an ECOG performance status of 0 or 1, received no prior treatment for advanced disease, and had adequate hematologic, live, or renal function. Those who received prior checkpoint inhibitors, traditional Chinese medicine with an antitumor effect, palliative radiation with 7 days of the first study drug dose, or a physical organ or blood system transplant, among other criteria, were excluded from enrollment.

The primary end point was PFS as assessed by the Independent Radiographic Review Committee (IRRC) based on RECIST v1.1 criteria. Secondary end points include OS, overall response rate, disease control rate, time to response, duration of response, and safety.

Prior phase 1b results of first-line sintilimab in combination with chemotherapy in patients with NSCLC demonstrated efficacy with a tolerable safety profile.³ Patients enrolled had treatment-naïve, unresectable, locally advanced, or metastatic nonsquamous or squamous histology, and were separated into cohorts of differing chemotherapy backbones. Patients were treated with sintilimab at 200 mg intravenously (IV) every 3 weeks in combination with pemetrexed at 500 mg/m² and cisplatin at 75 mg/m² IV every 3 weeks for 4 cycles in cohort D (n = 21). In cohort E, sintilimab was given in combination with gemcitabine at 1250 mg/m² on days 1 and 8 and IV cisplatin at 75 at mg/m² every 3 weeks for 6 cycles (n = 20).

The median follow-up was 11.4 months in cohort D and 10.3 months in cohort E. Results showed that the median PFS was 11.4 months (95% CI, 3.1—not available [NA]) in cohort D and was 6.5 months (95% CI, 5.3-8.0) in cohort E. The median OS was 18.9 months (95% CI, 5.3-18.9) and was not reached (95% CI, 10.3–NA) in cohorts D and E, respectively. Additionally, the 12-month OS rates were 68% and 64% in cohorts D and E, respectively.

Sintilimab injection was previously granted marketing approval by the NMPA for patients with relapsed/refractory classical Hodgkin lymphoma following second-line chemotherapy.

References

1. Tyvyt® (Sintilimab Injection) Combined with Gemzar® (Gemcitabine for Injection) and Platinum Chemotherapy Met the Predefined Primary Endpoint in the Phase 3 ORIENT-12 Study as First-Line Therapy in Patients with Locally Advanced or Metastatic Squamous Non-Small Cell Lung Cancer. Published May 6, 2020. https://prn.to/2WdVsKN. Accessed May 7, 2020.
2. Innovent and Eli Lilly Announce NMPA Acceptance of a Supplemental New Drug Application for Sintilimab in Combination with ALIMTA® (Pemetrexed) and Platinum as First-Line Therapy in Non-squamous NSCLC. https://prn.to/3ayqwJe. Published April 24, 2020. https://bit.ly/2FOrG6p. Accessed April 24, 2020.
3. Xu Nong, Ying K, Wang Z, et al. Phase Ib study of sintilimab in combination with chemotherapy for 1L advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(suppl_15). doi: 10.1200/JCO.2019.37.15_suppl.e20546.

There were no new safety signals with sintilimab compared to previous research with the PD-1 inhibitor. The data from the trial will be shared at a future medical meeting, Innovent Biologics and Eli Lilly and Company, the codevelopers of sintilimab, stated in a press release.