Crizotinib for Children & Young Adults With R/R, Systemic Anaplastic Large Cell Lymphoma
The FDA approved crizotinib for pediatric patients 1 year of age and older and young adults with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive. The safety and efficacy of crizotinib have not been established in older adults with R/R systemic ALK-positive ALCL.
Efficacy was evaluated in Study ADVL0912 (NCT00939770), a multicenter, single-arm, open-label trial in patients 1 to <=21 years of age that included 26 patients with R/R systemic ALK-positive ALCL after at least one systemic treatment. Patients received crizotinib 280 mg/m2 (20 patients) or 165 mg/m2 (6 patients) orally twice daily until disease progression or unacceptable toxicity. Patients were permitted to discontinue crizotinib to undergo hematopoietic stem cell transplantation.
Efficacy was based on objective response rate (ORR) and duration of response as assessed by an independent review committee. The ORR in the 26 patients was 88 percent (95% CI: 71, 96), with a complete remission rate of 81 percent. Of the 23 patients who achieved a response, 39 percent maintained response for at least 6 months, and 22 percent maintained response for at least 12 months.
Ocular toxicity (grade 1 or 2 visual disorders) occurred in 65 percent of patients with ALCL, gastrointestinal toxicity occurred in 92 percent, and serious adverse reactions occurred in 35 percent, most often from neutropenia and infection. The most common adverse reactions (>=5%), excluding laboratory abnormalities, were diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough, and pruritus. Grade 3-4 laboratory abnormalities (>=15%) were neutropenia, lymphopenia, and thrombocytopenia.
The recommended crizotinib dosage for systemic ALCL is 280 mg/m2 orally twice daily based on body surface area. Antiemetics are recommended prior to and during treatment with crizotinib in patients with ALCL. Due to the risk of visual loss, ophthalmologic evaluations are recommended at baseline and serially thereafter, coupled with monthly assessments of visual acuity and visual symptoms.
Fam-Trastuzumab Deruxtecan-Nxki for HER2-Positive Gastric Adenocarcinomas
Fam-trastuzumab deruxtecan-nxki has been approved by the FDA for adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
Efficacy was evaluated in a multicenter, open-label, randomized trial (DESTINY-Gastric01, NCT03329690) in patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy. A total of 188 patients were randomized (2:1) to receive fam-trastuzumab deruxtecan-nxki 6.4 mg/kg intravenously every 3 weeks or physician's choice of either irinotecan or paclitaxel monotherapy.
The main efficacy outcome measures were overall survival (OS) and objective response rate (ORR) assessed by independent central review (RECIST 1.1) in the intent-to-treat population. Additional efficacy outcome measures were progression-free survival (PFS) and duration of response (DOR).
OS was 12.5 months (95% CI: 9.6, 14.3) in the fam-trastuzumab deruxtecan-nxki arm compared with 8.4 months (95% CI: 6.9, 10.7) in the irinotecan or paclitaxel arm (HR 0.59; 95% CI: 0.39, 0.88, p=0.0097). Confirmed ORR was 40.5 percent (95% CI: 31.8, 49.6) in the fam-trastuzumab deruxtecan-nxki arm compared with 11.3 percent (95% CI: 4.7, 21.9) for those receiving irinotecan or paclitaxel. Median PFS was 5.6 months (95% CI: 4.3, 6.9) in the fam-trastuzumab deruxtecan-nxki arm compared to median PFS of 3.5 months (95% CI: 2.0, 4.3) in the irinotecan or paclitaxel arm. Median DOR was 11.3 months (95% CI: 5.6, NR) versus 3.9 months (95% CI: 3.0, 4.9), respectively.
The most common (>= 20%) adverse reactions including laboratory abnormalities were anemia, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, hypokalemia, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. The prescribing information includes a boxed warning to advise health professionals of the risks of interstitial lung disease and embryo-fetal toxicity.
The recommended fam-trastuzumab deruxtecan-nxki dose for gastric cancer is 6.4 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
Accelerated Approval of Daratumumab + Hyaluronidase for Light Chain Amyloidosis
The FDA granted accelerated approval to daratumumab plus hyaluronidase in combination with bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed light chain (AL) amyloidosis.
Efficacy was evaluated in ANDROMEDA (NCT03201965), an open-label, randomized, active-controlled trial in 388 patients with newly diagnosed AL amyloidosis with measurable disease and at least one affected organ, according to consensus criteria. Patients were randomized to receive bortezomib, cyclophosphamide, and dexamethasone (VCd arm) or with daratumumab plus hyaluronidase (D-VCd arm).
The hematologic complete response (HemCR) rate based on established consensus response criteria as evaluated by an independent review committee was 42.1 percent for the D-VCd arm and 13.5 percent for the VCd arm (odds ratio=4.8; 95% CI: 2.9, 8.1; p<0.0001).
The prescribing information includes warnings and precautions that serious or fatal cardiac adverse reactions occurred in patients with AL amyloidosis who received daratumumab plus hyaluronidase in combination with bortezomib, cyclophosphamide, and dexamethasone. Daratumumab plus hyaluronidase is not indicated and not recommended for the treatment of patients with AL amyloidosis who have NYHA Class IIIB or Class IV cardiac disease or Mayo Stage IIIB outside of controlled clinical trials.
The most common adverse reactions (>=20%) in patients with AL amyloidosis who received the D-VCd regimen are upper respiratory tract infection, diarrhea, peripheral edema, constipation, peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea, and cough.
The recommended daratumumab plus hyaluronidase dose is (1,800 mg daratumumab and 30,000 units hyaluronidase) administered subcutaneously into the abdomen over approximately 3-5 minutes according to recommended schedule in combination with VCd.
Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma
The combination of nivolumab and cabozantinib as first-line treatment for patients with advanced renal cell carcinoma (RCC) has received FDA approval.
Efficacy was evaluated in CHECKMATE-9ER (NCT03141177), a randomized, open-label trial in patients with previously untreated advanced RCC. Patients were randomized to receive either nivolumab 240 mg over 30 minutes every 2 weeks in combination with cabozantinib 40 mg orally once daily (n=323), or sunitinib 50 mg orally daily for the first 4 weeks of a 6-week cycle (4 weeks on treatment followed by 2 weeks off) (n=328).
The trial demonstrated a statistically significant improvement in progression-free survival (PFS), overall survival (OS), and confirmed overall response rate (ORR) for patients treated with nivolumab plus cabozantinib compared with those who received sunitinib. Median PFS per blinded independent central review (BICR) was 16.6 months versus 8.3 months; HR 0.51 (95% CI: 0.41, 0.64). Median OS was not reached in either arm; HR 0.60 (95% CI: 0.40, 0.89). Confirmed ORR per BICR was 55.7 percent and 27.1 percent in the nivolumab plus cabozantinib and sunitinib arms, respectively.
The most common adverse reactions (>= 20%) in patients receiving the combination of nivolumab and cabozantinib were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia syndrome, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.
The recommended dose is nivolumab 240 mg every 2 weeks (30-minute IV infusion) or 480 mg every 4 weeks (30-minute IV infusion) in combination with cabozantinib 40 mg orally once daily without food until disease progression or unacceptable toxicity.
Orphan Drug Designation of PVSRIPO for the Treatment of Advanced Melanoma
The FDA granted orphan drug designation for PVSRIPO for the treatment of advanced melanoma (stage IIB-IV). It is a novel viral immunotherapy, based on the Sabin type 1 polio vaccine, that activates a patient's innate and adaptive immune system to facilitate an anti-tumor response and establish long-term immunologic memory to help prevent the cancer's return.
Currently, researchers are recruiting for LUMINOS-102, a Phase II open-label, randomized trial (NCT04577807) in patients with advanced, unresectable melanoma who previously failed anti-PD1 therapy. This study will characterize the safety, tolerability, and initial efficacy of PVSRIPO intratumoral injection alone and in combination with a PD-1 inhibitor. The first patient is expected to be dosed in the first quarter of 2021.
LUMINOS-102 follows a successful Phase I monotherapy study of PVSRIPO in anti-PD1 refractory advanced melanoma in which patients who received three injections (6/12) had an overall response rate of 67 percent (4/6).
PVSRIPO aims to address the significant unmet need in advanced melanoma, since most patients are treated with checkpoint inhibitors, and many do not respond or later become resistant and require other options, which are limited.
Orphan drug designation is granted by the FDA Office of Orphan Products Development to drugs or biological products intended for the treatment of rare diseases or conditions that impact fewer than 200,000 people in the U.S. This designation acts as a stimulus for the development of drugs for rare diseases through several incentives, including eligibility for federal grants, research and development tax credits, waiver of filing fees, and the potential for a 7-year marketing exclusivity period after FDA approval.
Nivolumab for Resected Esophageal or Gastroesophageal Junction Cancer
The FDA accepted a supplemental Biologics License Application for nivolumab for the treatment of patients with resected esophageal or gastroesophageal junction (GEJ) cancer in the adjuvant setting, after neoadjuvant chemoradiation therapy (CRT). The FDA granted the application Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) goal date of May 20, 2021.
The filing was based on results from the Phase III CheckMate-577 trial, which is the first trial to show positive results in the adjuvant setting in this group of patients. The study met its primary endpoint of disease-free survival (DFS) in patients with esophageal or GEJ cancer, following neoadjuvant CRT and tumor resection. Results from the CheckMate-577 trial place esophageal and GEJ cancer among four tumor types-in addition to melanoma, bladder, and non-small cell lung cancer-for which nivolumab has shown a benefit in the early disease setting. The safety profile of nivolumab as adjuvant therapy in the CheckMate-577 trial was consistent with that reported in previous studies.
CheckMate-577 is a randomized, multicenter, double-blind study evaluating nivolumab as an adjuvant therapy in patients with resected esophageal or GEJ cancer who have received neoadjuvant CRT and have not achieved a pathological complete response. The primary endpoint of the trial is DFS and the secondary endpoint is overall survival (OS). Following neoadjuvant CRT and complete tumor surgical resection (also known as trimodality therapy), a total of 794 patients were randomized to receive placebo (n=262) or nivolumab (n=532) 240 mg by intravenous infusion every 2 weeks for 16 weeks, followed by placebo or nivolumab 480 mg every 4 weeks until disease recurrence, unacceptable toxicity, or withdrawal of consent, with a maximum of 1 year total treatment duration. Follow-up for OS is ongoing.
Fast Track Designation Granted to Padeliporfin ImPACT
The FDA granted Fast Track designation to padeliporfin ImPACT for the treatment of adult patients with low-grade and unifocal high-grade upper tract urothelial cancer (UTUC). This swiftly follows clearance of the Investigational New Drug application granted in December 2020, allowing initiation of the pivotal Phase III clinical trial of padeliporfin ImPACT in patients with low-grade UTUC, expected to begin enrollment in Q1 2021.
Padeliporfin ImPACT (immune photo activated cancer therapy) offers surgery-like efficacy combined with organ preservation. It is an oncology platform comprising the intravenous delivery of an inactive drug, padeliporfin. Upon activation, the drug rapidly triggers the constriction of the blood supply in the illuminated area only, resulting in targeted tumor necrosis that activates anti-tumor immunity and enhances cancer cell eradication.