FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint inhibitors for the Treatment of Biliary Tract Cancer.

On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials, which randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial the median OS of patients receiving durvalumab was 12.8 months (95% confidence interval [CI] 11.1, 14.0) and 11.5 months (95% CI 10.1, 12.5) in patients receiving placebo (HR 0.80 [95% CI 0.66, 0.97]). In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI 11.5, 13.6) and 10.9 months (95% CI 9.9, 11.6) in patients receiving placebo (HR 0.83 [95% CI 0.72, 0.95]). The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic option for these patients.

FDA Approval Summary: Repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer.

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro®, Bristol Myers Squibb Corporation), for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC, (NCT03093116), who were either treatment naïve or had received prior ROS1 TKI and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors (RECIST) version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI 68, 88); median duration of response was 34.1 months (95% CI 26, NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI 25, 52). The median duration of response was 14.8 months (95% CI 7.6, NE) BICR-assessed responses were observed in CNS metastases in patients in both cohorts, and in patients who developed resistance mutations following prior TKI therapy. The most common (> 20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

US Food and Drug Administration Approval Summary: Eflornithine for High-Risk Neuroblastoma After Prior Multiagent, Multimodality Therapy.

On December 13, 2023, the US Food and Drug Administration (FDA) approved eflornithine (IWILFIN, US WorldMeds) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. The approval was based on an externally controlled trial (ECT) consisting of a single-arm trial, study 3(b), compared with an external control (EC) derived from a National Cancer Institute/Children's Oncology Group-sponsored clinical trial (Study ANBL0032) and supported by confirmatory evidence. In the protocol-specified primary analysis, the event-free survival hazard ratio (HR) was 0.48 (95% CI, 0.27 to 0.85) and overall survival HR was 0.32 (95% CI, 0.15 to 0.70). The most common adverse reactions (≥5%) were hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. Notably, this is the first oncology drug approval which relies on an ECT as the primary clinical data to support substantial evidence of effectiveness. This was made possible by a distinctly high-quality, comparable EC data set with consistent treatment effect estimations demonstrated in multiple sensitivity and supportive analyses. Eflornithine's manageable safety profile and strong nonclinical and mechanistic data provided further support for the approval, and the evidentiary package was evaluated in the context of high unmet need in a rare, life-threatening cancer.

Correlations of response rate and progression-free survival with overall survival in immunotherapy trials for metastatic non-small-cell lung cancer: an FDA pooled analysis.

BACKGROUND: Radiographic changes might not fully capture the treatment effects of immune checkpoint inhibitors (ICIs). We aimed to assess correlations of overall response rate and progression-free survival with overall survival in trials of ICIs for metastatic non-small-cell lung cancer (NSCLC). METHODS: To assess trial-level and patient-level correlations of overall response rate and progression-free survival with overall survival, we conducted a pooled analysis of first-line randomised trials (including patients aged ≥18 years with metastatic squamous and non-squamous NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1) submitted to the US Food and Drug Administration from June 24, 2016, to March 16, 2021. Eligible trials evaluated at least one ICI in the experimental group versus chemotherapy in the control group. At the trial level, we used weighted linear regression to derive coefficients of determination (R2). At the patient level, we used Cox proportional hazards models to compare overall survival between responders versus non-responders per Response Evaluation Criteria in Solid Tumours (version 1.1). FINDINGS: A total of 13 trials including 9285 patients evaluated ICIs alone or in combination with chemotherapy versus chemotherapy alone. At the trial level, the R2 was 0·61 (95% CI 0·32-0·84) for correlation of overall response rate with overall survival and 0·70 (0·40-0·89) for correlation of progression-free survival with overall survival. Correlations ranged from weak to moderate when evaluating subgroups by PD-L1 expression and were consistent across trials evaluating ICIs alone or in combination with chemotherapy. At the patient level, responders had longer overall survival than non-responders (hazard ratio [HR] 0·28 [95% CI 0·26-0·30]). Among responders, overall survival was longer in patients enrolled in experimental groups than in control groups (HR 0·54 [95% CI 0·48-0·61]). INTERPRETATION: Correlations of overall response rate and progression-free survival with overall survival were generally moderate in this pooled analysis. The findings support routine analysis of mature overall survival data, where feasible, in first-line randomised trials of ICIs for metastatic NSCLC. FUNDING: US Food and Drug Administration.

FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma.

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.

FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum.

On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients 2 years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiologic response rate at week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiologic response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% [95% confidence interval (CI), 14-44] had a radiologic response at week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Furthermore, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis, and hyperglycemia.

FDA Approval Summary: Selpercatinib for the Treatment of Advanced RET Fusion-Positive Solid Tumors.

On September 21, 2022, the FDA granted accelerated approval to selpercatinib (Retevmo, Eli Lilly and Company) for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval was based on data from Study LOXO-RET-17001 (LIBRETTO-001; NCT03157128), an international, non-randomized, multi-cohort clinical trial that included patients with advanced solid tumors harboring RET alterations. The overall response rate in 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than non-small cell lung cancer (NSCLC) or thyroid cancer was 44% [95% confidence interval (CI), 28%-60%], with median duration of response 24.5 months (95% CI, 9.2-not evaluable). Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses, including patients with the following tumors: pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft-tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The recommendation for approval was supported by results from LIBRETTO-001 in patients with RET fusion-positive NSCLC and thyroid cancer, which formed the basis of prior approvals in these tumor types. The most common adverse reactions (>25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. This is the first tissue-agnostic approval of a RET-directed targeted therapy.

FDA Approval Summary: Amivantamab for the Treatment of Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

The FDA granted accelerated approval for amivantamab-vmjw (hereafter referred to as amivantamab), a bispecific antibody directed against EGFR and mesenchymal-epithelial transition receptor, on May 21, 2021, for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Approval was based on results of an ongoing, multicenter, nonrandomized, open-label, multicohort clinical trial (CHRYSALIS, NCT02609776), demonstrating a substantial overall response rate (ORR) and durable responses, with an ORR of 40% [95% confidence interval (CI): 29-51] and a median response duration of 11.1 months (95% CI: 6.9-not evaluable). Guardant360 CDx was contemporaneously approved as a companion diagnostic for this indication to identify EGFR exon 20 insertion mutations in plasma specimens. The most notable safety finding was the high incidence (66%) of infusion-related reactions, which is addressed in both the Dosage and Administration and Warnings and Precautions sections of the product label. Other common adverse reactions (occurring in ≥20% of patients) were rash, paronychia, musculoskeletal pain, dyspnea, nausea and vomiting, fatigue, edema, stomatitis, cough, and constipation. The approval of amivantamab was the first approval of a targeted therapy for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations.

FDA Approval Summary: Atezolizumab as Adjuvant Treatment following Surgical Resection and Platinum-Based Chemotherapy for Stage II to IIIA NSCLC.

On October 15, 2021, the FDA approved atezolizumab as adjuvant therapy in patients with stage II to IIIA non-small cell lung cancer (NSCLC) whose tumors have programmed cell death ligand 1 (PD-L1) expression on ≥1% of tumor cells (TC), as detected by an FDA-approved test. The approval was based on results from the IMpower010 trial, in which 1,005 patients with NSCLC who had completed tumor resection and cisplatin-based adjuvant chemotherapy were randomly assigned 1:1 to receive atezolizumab for 16 cycles or best supportive care. The primary endpoint of disease-free survival (DFS) as assessed by investigator was tested hierarchically in the following analysis populations: stage II-IIIA NSCLC with PD-L1 expression on ≥1% of TCs (PD-L1 ≥ 1% TC); all randomly assigned patients with stage II-IIIA NSCLC; and the intent-to-treat population comprising all randomly assigned patients. At the prespecified interim DFS analysis, IMpower010 demonstrated a statistically significant and clinically meaningful improvement in DFS in the stage II-IIIA PD-L1 ≥ 1% TC analysis population, with an HR of 0.66 (95% confidence interval, 0.50-0.88; P = 0.004) favoring the atezolizumab arm. The safety profile of atezolizumab was generally consistent with known toxicities of anti-PD-(L) antibodies. The VENTANA PD-L1 (SP263) Assay (Ventana Medical Systems, Inc.) was contemporaneously approved as a companion diagnostic device to select patients with NSCLC who are PD-L1 ≥ 1% TC for adjuvant treatment with atezolizumab. Atezolizumab is the first immune checkpoint inhibitor approved by FDA for the adjuvant treatment of NSCLC.

The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non-Small Cell Lung Cancer Treated With a PD-1/PD-L1 Blocking Antibody Using Real-World and Trial Data.

Clinical trials have demonstrated the benefit of PD-1/PD-L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1/PD-L1 blocking antibodies in real-world data (RWD; patient-level data from electronic health records) and pooled clinical trial data submitted to the US Food and Drug Administration (FDA). The Kaplan-Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis-generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and hold promise to complement trial data in better understanding populations not represented in clinical trials.

FDA Approval Summary: Mobocertinib for Metastatic Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations.

On September 15, 2021, the FDA granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788-15-101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial that included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% [95% confidence interval (CI), 20%-37%] with a median duration of response of 17.5 months (95% CI, 7.4-20.3). The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and torsades de pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation-positive NSCLC.

FDA Approval Summary: Pemigatinib for Previously Treated, Unresectable Locally Advanced or Metastatic Cholangiocarcinoma with FGFR2 Fusion or Other Rearrangement.

On April 17, 2020, the FDA granted accelerated approval to pemigatinib (PEMAZYRE, Incyte Corporation) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA-approved test. Approval was based on FIGHT-202 (NCT02924376), a multicenter open-label single-arm trial. Efficacy was based on 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least one prior therapy and had an FGFR2 gene fusion or rearrangement. Patients received pemigatinib, 13.5 mg orally, once daily for 14 consecutive days, followed by 7 days off therapy. Safety was based on a total of 466 patients, 146 of whom had cholangiocarcinoma and received the recommended dose. Efficacy endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent review committee using RECIST 1.1. ORR was 36% (95% confidence interval: 27-45). Median DOR was 9.1 months. The most common adverse reactions were hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. Ocular toxicity and hyperphosphatemia are important risks of pemigatinib. The recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles. FDA also approved the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.

FDA Approval Summary: Nivolumab for the Adjuvant Treatment of Adults with Completely Resected Esophageal/Gastroesophageal Junction Cancer and Residual Pathologic Disease.

The FDA approved nivolumab on May 20, 2021, for the adjuvant treatment of completely resected (negative margins) esophageal or gastroesophageal junction cancer (EC/GEJC) in patients who had residual pathologic disease following chemoradiotherapy. The approval was based on data from the double-blind CheckMate 577 trial, which randomly allocated patients to receive nivolumab or placebo. Disease-free survival (DFS) was the primary endpoint. At the time of the final DFS analysis and the prespecified interim overall survival (OS) analysis, the estimated median DFS was 22.4 months [95% confidence interval (CI), 16.6-34.0] in the nivolumab arm versus 11.0 months (95% CI, 8.3-14.3) in the placebo arm, with an HR of 0.69 (95% CI, 0.56-0.85; two-sided P value = 0.0003). An unblinded review of OS did not indicate a detrimental effect on survival. Adverse reactions occurring in ≥20% of patients receiving nivolumab were fatigue/asthenia, diarrhea, nausea, rash, musculoskeletal pain, and cough. Approval of nivolumab is likely to change the treatment paradigm for the adjuvant treatment of patients with completely resected (negative margins) EC/GEJC who have residual pathologic disease following chemoradiotherapy based on the study results and favorable risk:benefit of nivolumab administration.

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer.

On September 17, 2021, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor were treated with either cabozantinib 60 mg orally once daily (N = 170) or placebo with best supportive care (N = 88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review per RECIST 1.1. The median PFS was 11.0 months [95% confidence interval (CI), 7.4-13.8] in the cabozantinib arm compared with 1.9 months (95% CI, 1.9-3.7) in the control arm, with an HR of 0.22 (95% CI, 0.15-0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia, which was added as a warning in the product labeling.

FDA Approval Summary: Pembrolizumab, Atezolizumab, and Cemiplimab-rwlc as Single Agents for First-Line Treatment of Advanced/Metastatic PD-L1-High NSCLC.

FDA's approval of cemiplimab-rwlc on February 22, 2021, follows prior approvals of pembrolizumab and atezolizumab for similar indications as first-line treatment for patients with programmed death ligand-1 (PD-L1)-high advanced non-small cell lung cancer (NSCLC). Approvals of these anti-PD-L1 agents were supported by statistically significant and clinically meaningful improvements in overall survival (OS) in international, multicenter, active-controlled randomized trials. In KEYNOTE-024, the OS HR was 0.60 [95% confidence interval (CI), 0.41-0.89; P = 0.005] favoring pembrolizumab over platinum-doublet chemotherapy. In IMpower110, the OS HR was 0.59 (95% CI, 0.40-0.89; P = 0.0106) favoring atezolizumab over platinum-doublet chemotherapy. In Study 1624, the OS HR was 0.68 (95% CI, 0.53-0.87; P = 0.0022) favoring cemiplimab-rwlc over platinum-doublet chemotherapy. The progression-free survival (PFS) effect sizes for these anti-PD-L1 antibodies were also comparable across their respective registrational trials, and their safety profiles were consistent with the anti-PD-L1 class adverse event profile. The consistent survival benefits and manageable toxicity profiles of these single-agent anti-PD-L1 antibodies have established them as important treatment options in the PD-L1-high NSCLC treatment landscape. FDA approvals of these anti-PD-L1 antibodies, based on their favorable benefit-risk profiles, present effective chemotherapy-free therapeutic options for patients with advanced PD-L1-high NSCLC in the United States.

The Friends of Cancer Research Real-World Data Collaboration Pilot 2.0: Methodological Recommendations from Oncology Case Studies.

The purpose of this study was to evaluate the potential collective opportunities and challenges of transforming real-world data (RWD) to real-world evidence for clinical effectiveness by focusing on aligning analytic definitions of oncology end points. Patients treated with a qualifying therapy for advanced non-small cell lung cancer in the frontline setting meeting broad eligibility criteria were included to reflect the real-world population. Although a trend toward improved outcomes in patients receiving PD-(L)1 therapy over standard chemotherapy was observed in RWD analyses, the magnitude and consistency of treatment effect was more heterogeneous than previously observed in controlled clinical trials. The study design and analysis process highlighted the identification of pertinent methodological issues and potential innovative approaches that could inform the development of high-quality RWD studies.

FDA Approval Summary: Nivolumab in Combination with Ipilimumab for the Treatment of Unresectable Malignant Pleural Mesothelioma.

On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years (n = 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed (n = 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months [95% confidence interval (CI), 16.8-21.5] compared with 14.1 months (95% CI: 12.5-16.2; HR, 0.74; 95% CI, 0.61-0.89; P = 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.

FDA Approval Summary: Capmatinib and Tepotinib for the Treatment of Metastatic NSCLC Harboring MET Exon 14 Skipping Mutations or Alterations.

The FDA approved capmatinib and tepotinib on May 6, 2020, and February 3, 2021, respectively. Capmatinib is indicated for patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors have a mutation leading to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Tepotinib is indicated for mNSCLC harboring MET exon 14 skipping alterations. The approvals were based on trials GEOMETRY mono-1 (capmatinib) and VISION (tepotinib). In GEOMETRY mono-1, overall response rate (ORR) per Blinded Independent Review Committee (BIRC) was 68% [95% confidence interval (CI), 48-84] with median duration of response (DoR) 12.6 months (95% CI, 5.5-25.3) in 28 treatment-naïve patients and 41% (95% CI: 29, 53) with median DoR 9.7 months (95% CI, 5.5-13) in 69 previously treated patients with NSCLC with mutations leading to MET exon 14 skipping. In VISION, ORR per BIRC was 43% (95% CI: 32, 56) with median DoR 10.8 months (95% CI, 6.9-not estimable) in 69 treatment-naïve patients and 43% (95% CI, 33-55) with median DoR 11.1 months (95% CI, 9.5-18.5) in 83 previously-treated patients with NSCLC harboring MET exon 14 alterations. These are the first two therapies to be FDA approved specifically for patients with metastatic NSCLC with MET exon 14 skipping.

FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC.

On May 28, 2021, the FDA granted accelerated approval to sotorasib (Lumakras, Amgen) for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with a Kirsten rat sarcoma proto-oncogene (KRAS) G12C mutation who have received at least one prior systemic therapy. The approval was based on CodeBreaK 100 (Study 20170543), a dose-escalation and dose-expansion trial in patients with an advanced, KRAS G12C-mutated, solid tumor. The overall response rate (ORR) observed in patients with KRAS G12C-mutated NSCLC treated with sotorasib (n = 124) was 36% [95% confidence interval (CI), 28-45]. The median duration of response was 10.0 months (95% CI, 6.9-not estimable). The most common adverse reactions (≥20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. This is the first approval of a targeted therapy for KRAS G12C-mutated NSCLC. Because of pharmacokinetic data and ORRs of patient cohorts who took sotorasib at lower doses in the dose-escalation portion of CodeBreaK 100, a dose comparison study is being conducted as a post-marketing requirement.