FDA Grants Pembrolizumab Priority Review for Advanced SCLC

Jonathan Cheng, MD

Jonathan Cheng, MD

The FDA has granted a priority review designation to a supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) as a treatment for patients with advanced small cell lung cancer (SCLC) whose disease has progressed following ≥2 prior lines of therapy.¹

UPDATE 6/18/2019: FDA Approves Pembrolizumab for Metastatic SCLC

The application is based on findings from cohorts of the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 studies, in which pembrolizumab elicited 19% and 33% overall response rates (ORRs) in patients with advanced and extensive-stage SCLC, respectively.^2,3 Under the Prescription Drug User Fee Act, the FDA will make a decision on the sBLA on or before June 17, 2019.

“There is a significant need for new treatment options for small cell lung cancer, which has a 5-year survival rate of only 6% overall,” said Jonathan Cheng, MD, vice president, oncology clinical research, Merck Research Laboratories, the developer of the PD-1 inhibitor. “Keytruda has already been established as an important treatment option for many patients with advanced non—small cell lung cancer and this acceptance provides an opportunity to potentially benefit even more patients.”

In the phase II KEYNOTE-158 basket study (NCT02628067), patients with 10 tumor types plus microsatellite instability—high (MSI-H) cancers, including advanced SCLC, were enrolled regardless of biomarker status. Patients were treated with pembrolizumab at 200 mg intravenously (IV) every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or study withdrawal. Patients were followed up for survival. The primary endpoint was centrally-reviewed ORR by RECIST v1.1 criteria; secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response, and safety. Efficacy in biomarker subgroups was an exploratory endpoint.

To be eligible for enrollment in the SCLC cohort, patients had unresectable and/or metastatic disease, progression on or intolerance to standard therapy, an ECOG performance status of 0 or 1, ≥1 measurable lesion, evaluable tumor sample for biomarker assessments, and no autoimmune disease or noninfectious pneumonitis.

In the SCLC cohort (n = 107), the median age was 63 years (range, 24-84) and 75 patients were male. Thirty-five percent (n = 37) and 65% of patients had an ECOG performance status of 0 and 1, respectively. Fifteen percent (n = 16) of patients had brain metastases. Regarding histology, 1% (n = 1) had carcinoid tumors, 7% (n = 7) had neuroendocrine tumors, and 93% (n = 99) had small cell carcinoma. One patient had previously received neoadjuvant/adjuvant therapy, 45 (n = 42) received 1, 34% (n = 36) received 2, and 23% (n = 25) received ≥3 prior treatments.

Additionally, 39% (n = 42) of tumors were PD-L1 positive, 47% (n = 50) were PD-L1 negative, and 14% of patients were nonevaluable. Ninety-one percent of tumors were not MSI-H, and 9% were nonevaluable.

At a median follow-up of 9.3 months (range, 0.5-22.3) of the 107 patients, results showed that the ORR was 18.7% (95% CI, 11.8-27.4); this included 3 complete responses (CRs), 17 partial responses (PRs), and 12 cases of stable disease. Sixty-two patients had progressive disease; the disease control rate was 30%. The median duration of response was not reached (range, 2.1+ to 18.7+).

The median PFS was 2.0 months (95% CI, 1.9-2.1) and the median OS was 8.7 months (95% CI, 5.6-12.0).

The responses were higher in the PD-L1—positive population, with a 35.7% ORR (95% CI, 21.6-52.0) compared with a 6.0% ORR (95% CI, 1.3-16.5) in the PD-L1–negative group. Median PFS was comparable in both arms with 2.1 months (95% CI, 2.0-8.1) and 1.9 months (95% CI, 1.6-2.0) in the PD-L1–positive and –negative groups, respectively. However, the median OS was higher in the PD-L1–positive subset (14.9 months; 95% CI, 5.6-NR) versus those who were PD-L1 negative (5.9 months; 95% CI, 3.3-10.1).

Regarding safety, all-grade adverse events (AEs) occurred in 60% of patients, with AEs occurring in ≥10% of patients being fatigue (14%), pruritis (12%), hypothyroidism (12%), decreased appetite (10%), and nausea (10%). Twelve percent of patients experienced grade 3/4 AEs; grade 3/4 pancreatitis occurred in 2% of patients. Additionally, 2 fatal treatment-related AEs, pneumonia and encephalopathy, occurred during the safety follow-up.

All-grade immune-mediated AEs and infusion reactions included hypothyroidism (12%), hyperthyroidism (7%), severe skin reactions (3%), adrenal insufficiency (2%), nephritis (2%), pancreatitis (2%), pneumonitis (2%), colitis (1%), infusion reactions (1%), and thyroiditis (1%). Grade 3 immune-mediated AEs that occurred at 1% were severe skin reactions, adrenal insufficiency, pneumonitis, and colitis; grade 3 immune-mediated pancreatitis occurred in 2% of patients.

In the international, nonrandomized, multi-arm, phase Ib KEYNOTE-028 basket trial (NCT02054806), investigators evaluated the safety and efficacy of pembrolizumab in patients with advanced solid tumors.

The SCLC cohort comprised 163 patients who were screened for enrollment from March 2014 to May 2015, 145 of whom had biopsy samples for PD-L1 evaluation. Forty-six patients (31.7%) tested positive for PD-L1 expression, but 15 did not meet inclusion criteria. Ultimately, 24 patients were treated.

The median age of the treated patients was 60.5 years (range, 41-80), and 14 (58.3%) of patients were men. All patients had received prior chemotherapy for SCLC, and 87.5% had received ≥2 prior lines of therapy. All patients had received prior platinum plus etoposide as frontline therapy, and 11 (45.8%) patients received second-line treatment with either topotecan or irinotecan.

Patients received 10 mg/kg of pembrolizumab every 2 weeks for 24 months or until progression, intolerable toxicity, physician decision to discontinue, or withdrawal of consent occurred.

At a median follow-up of 9.8 months (range, 0.5-24.4), results showed that pembrolizumab led to an ORR of 33% in patients with extensive-stage SCLC; 1 patient (4.2%) experienced a CR, 7 (29.2%) had PRs, and 1 (4.2%) had stable disease for <6 months. Thirteen patients (54.2%) experienced disease progression as the best overall response.

Median time to response was 2.0 months (range, 1.7-3.7) and the median duration of response was 19.4 months (range, ≥3.6 to ≥20.0). Additionally, the responses were durable, with 3 patients remaining on treatment at the time of data cutoff.

Moreover, the median PFS was 1.9 months (95% CI, 1.7-5.9), and the estimated 6-month PFS was 28.6% and estimated 12-month PFS was 23.8%. The median OS was 9.7 months (95% CI, 4.1-NR). The estimated 6- and 12-month OS rates were 66.0% and 37.7%, respectively.

Regarding safety, all patients experienced AEs; the most common all-grade AEs were asthenia (n = 7), fatigue (n = 7), cough (n = 6), arthralgia (n = 5), diarrhea (n = 5), insomnia (n = 5), and rash (n = 5).

Moreover, 16 patients (66.7%) experienced treatment-related AEs, the most common of which were arthralgia, asthenia, and rash (n = 4 each), as well as diarrhea and fatigue (n = 3 each). Eight patients (33.3%) had grade ≥3 AEs, 2 of whom had AEs that were determined to be related to treatment. One patient experienced grade 3 bilirubin elevation, and another experienced grade 3 asthenia and grade 5 colitis/intestinal ischemia.

One other patient experienced grade 2 autoimmune thyroiditis, and 1 patient experienced a grade 1 infusion-related reaction that occurred during cycle 2 and resolved upon interruption of pembrolizumab. The reaction recurred during cycle 3 and again resolved with pembrolizumab interruption. That patient subsequently discontinued treatment due to disease progression.

Pembrolizumab is also being explored in combination with etoposide and platinum-based chemotherapy in patients with newly diagnosed, extensive-stage SCLC in the ongoing phase III KEYNOTE-604 study (NCT03066778).

References

1. FDA Grants Priority Review to Merck’s Supplemental Biologics License Application for KEYTRUDA® (pembrolizumab) Monotherapy for Third-Line Treatment of Patients with Advanced Small Cell Lung Cancer (SCLC). Merck. Published February 20, 2019. https://bit.ly/2TTkawm. Accessed February 20, 2019.
2. Chung HC, Lopez-Martin J, Kao S, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer: KEYNOTE-158. J Clin Oncol. 2018;36 (suppl; abstr 8506). doi: 10.1200/JCO.2018.36.15_suppl.8506.
3. Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35(34):3823-3829. doi: 10.1200/JCO.2017.72.5069.