Treatment options for cancer patients are increasing. In May, a considerable number of new cancer treatments and extended indications were approved by the United States (US) Food and Drug Administration (FDA). An impressive seven of these were for the treatment of non-small cell lung cancer (NSCLC).

Two First-Line Indications for Nivolumab Plus Ipilimumab Combination in Advanced NSCLC.

The first approved indication of the combination of nivolumab plus ipilimumab (Opdivo® plus Yervoy®, Bristol-Myers Squibb Co.) in advanced NSCLC is for first-line treatment of patients with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations whose tumors express PD-L1 ≥1%, as determined by the simultaneously approved companion diagnostic test (PD-L1 IHC 28-8 pharmDx, Agilent Technologies, Inc.). Approval was based on efficacy data from the randomized, open-label, phase III CHECKMATE-227 trial that included 793 patients with tumor expression of PD-L1 ≥1% who received either the immunotherapy combination or platinum-doublet chemotherapy. Median overall survival (OS) was significantly extended with the combination treatment versus chemotherapy alone (17.1 versus 14.9 months (HR 0.79; P=0.0066). The second first-line indication of nivolumab plus ipilimumab in advanced NSCLC with no EGFR or ALK alterations is in combination with 2 cycles of platinum-doublet chemotherapy.This approval was based on results from the randomized, open-label, phase III CHECKMATE-9LA trial that included 719 patients and compared the above combination with 4 cycles of platinum-doublet chemotherapy. These results were presented at the ASCO virtual meeting in 2020. The combination of nivolumab plus ipilimumab and 2 cycles of chemotherapy compared with chemotherapy alone significantly improved median OS at interim analysis (14.1 versus 10.7 months; HR 0.69, P=0.0006). With a minimum follow-up of 12 months, OS was further improved (HR 0.66). The magnitude of the clinical benefit with the combination of immunotherapy and 2 cycles of chemotherapy was consistent across subgroups, regardless of tumor histology or PD-L1 expression. 

Additional Indication of Atezolizumab in Advanced NSCLC with High PD-L1 Expression in a First-Line Setting.

Atezolizumab (Tecentriq®, Genentech Inc.) received approval for first-line treatment of patients with advanced NSCLC with high PD-L1 expressing tumors (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells covering ≥ 10% of the tumor area [IC ≥ 10%]) with no EGFR or ALK  genomic aberrations. Approval was based on the open-label, randomized, phase III IMpower110 trial that compared efficacy and safety of first-line atezolizumab monotherapy with platinum-based chemotherapy in 572 patients with PD-L1 positive advanced NSCLC. In patients with TC ≥ 50% or IC ≥ 10%, atezolizumab monotherapy extended the median OS by 7.1 months compared with chemotherapy (20.2 months versus 13.1 months; HR 0.59; P=0.0106). The safety profile also favored atezolizumab. The FDA simultaneously approved the Ventana PD-L1 Assay (SP142; Ventana Medical Systems, Inc.), a companion diagnostic to determine PD-L1 expression.

Brigatinib Indication Extended to First-Line Therapy in ALK-Positive NSCLC.

Brigatinib (Alunbrig®, ARIAD Pharmaceuticals Inc.) was approved for patients with ALK-positive metastatic NSCLC, as determined by the FDA-approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc.), based on efficacy data from the open-label, phase III ALTA-1L trial. The trial randomized 275 patients with ALK-positive NSCLC, who had not been previously treated with ALK-targeted therapy, to brigatinib or crizotinib. Estimated progression-free survival (PFS) per blinded independent review committee (BIRC), the primary endpoint, was 24 months for patients treated with brigatinib versus 11 months for crizotinib (HR 0.49; P<0.0001). The safety profile of brigatinib was consistent with previous studies.

Capmatinib for NSCLC With METex14 Skipping Mutations.

Accelerated approval was granted to capmatinib (Tabrecta™, Novartis) for patients with advanced NSCLC whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping, as detected by the FDA-approved FoundationOne CDx assay (Foundation Medicine, Inc.). The approval was granted based on efficacy data from the non-randomized, open-label, phase II GEOMETRY mono-1 trial. The trial included 97 patients with metastatic NSCLC and confirmed MET exon 14 skipping mutations in 28 treatment-naïve patients and 69 previously treated patients. ORR, per BIRC, and response duration (DOR) were the primary endpoints; ORR was 68% in treatment-naïve patients with DOR of 12.6 months, and in previously treated patients the ORR was 41% with DOR of 9.7 months. Importantly, capmatinib also showed high efficacy in patients with brain metastases.

Ramucirumab Plus Erlotinib, Another First-Line Treatment Option for EGFR-Mutant Advanced NSCLC.

Ramucirumab (Cyramza®, Eli Lilly and Company) was approved in combination with erlotinib for first-line treatment of advanced NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations. This approval was based on results from the double-blind, placebo-controlled, phase III RELAY trial that randomized 449 patients to receive either ramucirumab or placebo in combination with erlotinib. Median PFS was 19.4 months in the ramucirumab plus erlotinib arm versus 12.4 months in the placebo plus erlotinib arm (HR 0.59; P<0.0001), median DOR was also 7 months longer with the combination.

Selpercatinib, the First Approved Targeted Therapy for Patients with RET-Positive Lung and Thyroid Cancers.

Accelerated approval was granted to selpercatinib (Retevmo™, Eli Lilly and Company), a highly selective and potent tyrosine kinase inhibitor, for patients with metastatic RET fusion-positive NSCLC and for adult and pediatric patients ≥12 years of age with advanced RET-mutant medullary thyroid cancer (MTC) or patients with RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine (RAI)-refractory. Approval was based on high response rates and durability of response in NSCLC and thyroid cancer cohorts of patients with RET alterations included in the phase I/II LIBRETTO-001 clinical trial. In the RET-fusion positive NSCLC cohort ORR was 68% for platinum pre-treated patients and 85% for treatment naïve. In the cohort of RET-mutant medullary thyroid cancer ORR was 69% for pretreated patients and 73% for treatment naïve patients. For small cohort of RET-fusion positive RAI refractory thyroid cancer who received previous systemic therapy ORR was 79% and was 100% for treatment naïve RAI refractory patients. In general, across all cohorts, majority of responding patients have response duration of 6 months or longer.

Additional Indication of Olaparib Maintenance in Ovarian Cancer in Combination with Bevacizumab.

Olaparib (Lynparza®, AstraZeneca Pharmaceuticals, LP) in combination with bevacizumab was approved for first-line maintenance treatment of patients with advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy, and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability. A companion diagnostic Myriad myChoice® CDx (Myriad Genetic Laboratories, Inc.) was also approved. This additional indication was based on results from the double-blind, placebo-controlled phase III PAOLA-1 trial, where 806 patients with response to first line therapy were randomized to receive maintenance therapy with either olaparib plus bevacizumab or placebo plus bevacizumab. For the subgroup of 387 patients with HRD-positive tumors who were treated with olaparib plus bevacizumab, median PFS was substantially extended compared with placebo plus bevacizumab (37.2 versus 17.7 months; HR 0.33).

Olaparib and Rucaparib Now Also Indicated for Metastatic Castration-Resistant Prostate Cancer (mCRPC).

Olaparibwas approved for patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated mCRPC, who have progressed following prior treatment with enzalutamide or abiraterone. The approval was based on results from the open-label, randomized, phase III PROfound trial that compared olaparib with a hormonal agent (enzalutamide or abiraterone plus prednisone) in two cohorts of patients (A and B) with mCRPC. Cohort A included patients with BRCA1, BRCA2 or ATM gene mutations while cohort B included patients with alterations in other HRR genes. The primary endpoint was independently reviewed radiographic PFS (rPFS) in cohort A. Results showed significantly longer rPFS with olaparib compared with hormonal therapy (7.4 versus 3.6 months; HR 0.34; P<0.0001); confirmed ORR and time to pain progression were also improved. A significant rPFS benefit with olaparib was also seen in the overall population (cohorts A and B). The companion diagnostic assays FoundationOne CDx (Foundation Medicine, Inc.) and BRACAnalysis CDx (Myriad Genetic Laboratories, Inc) for detecting HRR and BRCA1/2 alterations, respectively, were also approved. 

Another PARP inhibitor, rucaparib (Rubraca®, Clovis Oncology, Inc.) was granted accelerated approval for patients with deleterious BRCA mutatio (germline and/or somatic)-associated mCRPC who have been previously treated with androgen receptor-directed therapy and taxane-based chemotherapy. Efficacy data from the ongoing, single-arm phase II TRITON2 trial that demonstrated confirmed radiologic responses in 44% and confirmed prostate-specific antigen (PSA) responses in 51% of patients supported this approval. Responses were durable in more than a half of responding patients.

Ripretinib as Late-Line Treatment for Patients with Advanced GIST.

Ripretinib (Qinlok™, Deciphera Pharmaceuticals, LLC.) was approved for patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with ≥ 3 kinase inhibitors, including imatinib. The approval was based on efficacy data from the randomized, double-blind, placebo-controlled phase III INVICTUS trial that included 129 patients with GIST who had received prior treatment with imatinib, sunitinib, and regorafenib. Median PFS, per BIRC (primary endpoint), was significantly longer with ripretinib than with placebo (6.3 versus 1.0 month, HR 0.15, P<0.0001). In addition, data indicated a survival benefit with ripretinib, median OS was 15.1 versus 6.6 months (HR 0.36). Importantly, ripretinib was associated with a favorable toxicity profile.

Atezolizumab Plus Bevacizumab, a New First-line Option for Advanced HCC.

The combination of atezolizumab and bevacizumab (Tecentriq® and Avastin®, Genentech Inc.) was approved for patients with unresectable or metastatic HCC who have not received prior systemic therapy, based on survival improvement from the phase III IMbrave150 trial. The trial randomized 501 patients to receive atezolizumab plus bevacizumab or sorafenib. Median OS was not reached in the atezolizumab plus bevacizumab arm versus 13.2 months in sorafenib arm (HR 0.58). See more details on these results in the recent ACE OncoBlog.

Expanded Indication of Pomalidomide for Kaposi Sarcoma.

Pomalidomide (Pomalyst®, Celgene Corporation) was granted accelerated approval for the treatment of patients with AIDS-related Kaposi sarcoma after failure of highly active antiretroviral therapy (HAART) and for Kaposi sarcoma in HIV-negative adult patients. ORR results from the open-label, single arm Study 12-C-0047, conducted by the National Cancer Institute, provided the supporting data for this approval. Among the 18 HIV-positive patients who also continued HAART, ORR was 67% with a median DOR of 12.5 months. Among the 10 HIV-negative patients, ORR was 80% with a median DOR of 10.5 months.

Subcutaneous Formulation of Daratumumab for Multiple Myeloma.

Daratumumab and hyaluronidase-fihj (Darzalex Faspro™, Janssen Biotech, Inc.) was approved for subcutaneous dosing of patients with newly diagnosed or relapsed/refractory multiple myeloma based on efficacy data from the open-label, non-inferiority COLUMBA trial. Results showed that subcutaneous daratumumab was non-inferior to IV daratumumab in terms of efficacy and pharmacokinetics. ORR was 41.1% for subcutaneous daratumumab and 37.1% for daratumumab IV with a risk ratio of 1.11. The new formulation is approved for the same indications as intravenous (IV) daratumumab.