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Experts Reflect on the Most Impactful FDA Moves of 2019

Danielle Ternyila
Published Online:11:34 PM, Fri January 3, 2020
The FDA granted approval to countless treatments across cancer types throughout 2019 until the end of the year, with a final approval on December 31st for the use of a BRCA targeted therapy in pancreatic cancer. With the excitement of a new year of further advances, Targeted Oncology followers on Twitter shared their thoughts on some of the most impactful FDA approvals in 2019. Although there was comparable interest across lung, breast, and genitourinary cancers as well as hematologic malignancies, another major area of interest in 2019 was gastrointestinal cancers.
 
Following the vast amount of regulatory action on oncologic therapies, several experts shared their thoughts on the approvals they found to be most important in 2019, while others reflected on some of the advancements they are looking forward to in the new year.

“The newest trend in 2020 in the field of precision medicine is related to population health. New tools are available for blood tests to detect cancer at an early, treatable and often curable stage,” Stephen Gruber MD, PhD, MPH, director of the Center for Precision Medicine at City of Hope in Duarte, California, told Targeted Oncology. “Our crystal ball is also clearly showing that there is an increasing trend for patients to be monitored with liquid biopsies. Liquid biopsies detect early progression or resistant disease faster than other methods, and this is likely to be increasingly used in the United States for measuring residual disease and recurrence.”
 
Ajay Goel, PhD, MS, professor and chair in the Department of Molecular Diagnostics, Therapeutics and Translational Oncology at City of Hope, agreed that genomic testing will become more routine in 2020, which will result in the development of more immunotherapy treatments.

“Given the advances made in genomic sequencing, in the coming years, we’re going to see next-generation diagnostics being used. Expect to see more blood-based tests that can measure circulating DNA, RNA, or proteins that can be used as routine diagnostic testing for people whose family/genetic history puts them at high risk for certain diseases. These tests will become a lot more affordable. Cancer will be diagnosed earlier, which means physicians can intercept earlier and provide treatments earlier, resulting in better survival and treatment outcomes.”
 

Gastrointestinal Cancers


“This year was a big year for hepatocellular carcinoma (HCC) with 2 new FDA approvals, which is quite remarkable considering how difficult this patient population is to get through active therapy. Cabozantinib (Cabometyx) and ramucirumab (Cyramza) were both FDA approved after sorafenib (Nexavar) failure in different subsets of patients with HCC. This highlights the importance of the VEGFR2 pathway in the vascular growth in the treatment and proliferation of HCC,” Yelena Y. Janjigian, MD, chief of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, told Targeted Oncology

Cabozantinib for Hepatocellular Carcinoma
In January 2019, the FDA approved cabozantinib for the treatment of patients with HCC who previously received sorafenib. The approval was based on data from the phase III CELESTIAL trial, which demonstrated an improvement in overall survival (OS) by 2.2 months with cabozantinib versus placebo (HR, 0.76; 95% CI, 0.63-0.92; P = .0049).

Ramucirumab for Hepatocellular Carcinoma
Ramucirumab was approved by the FDA in May 2019 for the treatment of patients with HCC who have an alpha-fetoprotein of ≥400 ng/mL and have previously been treated with sorafenib. This approval was based on data from the phase III REACH-2 trial, where ramucirumab led to a median OS of 8.5 months versus 7.3 months with placebo in patients who progressed on or became intolerant to frontline sorafenib (HR, 0.71; 95% CI, 0.53-0.95, P = .020).

“The most exciting data is forthcoming, and it is the combination of these tumor-targeting antibodies and tyrosine kinase inhibitors in combination with anti–PD-1 therapy. There is an ongoing trial of atezolizumab (Tecentriq) plus cabozantinib and others. It was a big year for HCC, with more excitement and more data to come for combination strategies,” Janjigian said.

While 2 new approvals in the field of HCC are exciting, Janjigian also reviewed another agent that is demonstrating promise as treatment for patients with other gastrointestinal cancers.

“In gastric cancer and esophagus cancer, we had several FDA approvals,” Janjigian added. “TAS-102 (trifluridine/tipiracil; Lonsurf) is now FDA approved in gastric cancer after progression on multiple lines of therapy and has shown a positive result in later lines of therapy against placebo. It is a good option to consider if all options are exhausted.”

TAS-102 for Metastatic Gastric or GEJ Adenocarcinoma
In February 2019, TAS-102 received approval from the FDA for the treatment of adult patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who were previously treated with at least 2 prior lines of chemotherapy, including fluoropyrimidine, a platinum-based chemotherapy, either a taxane or irinotecan and, if appropriate, HER2/neu-targeted therapy. The approval was based on data from the phase III TAGS trial, which demonstrated the agent could reduce the risk of death by about one-third compared with placebo. There were also improvements in progression-free survival (PFS) and disease control.

“Of course, if a patient is functional and motivated, a clinical trial would always be preferred, particularly as there are a lot of options with immunotherapy in clinical trials,” Janjigian said. “In esophageal squamous cell carcinoma (ESCC), this was a practice-changing approval in the second-line setting where chemotherapy tends to not work well. We now have an FDA approval for pembrolizumab (Keytruda) in patients who are PD-L1–positive with a combined positive score (CPS) greater than 10.”

Pembrolizumab for Advanced/Metastatic Esophageal Squamous Cell Carcinoma
The FDA approved single-agent pembrolizumab in July 2019 as a treatment for patients with recurrent, locally advanced, or metastatic ESCC whose tumors express PD-L1 (CPS ≥10), as determined by an FDA-approved test, and who have disease progression after ≥1 prior systemic regimen. Patients within this population have limited treatment options. This single-agent option is the first anti–PD-1 therapy to be approved in this setting.

Olaparib for Metastatic Pancreatic Adenocarcinoma
As 2019 came to a close, the FDA approved the PARP inhibitor olaparib (Lynparza) as a treatment for patients with deleterious or suspected deleterious germline BRCA-mutant metastatic pancreatic adenocarcinoma who have not had disease progression on at least 16 weeks of frontline platinum-based chemotherapy. This marks the first BRCA targeted therapy to be approved in pancreatic cancer. The decision was based on data from the phase III POLO trial, which demonstrated a median PFS of 7.4 months versus 3.8 months with placebo (HR, 0.53; 95% CI, 0.35-0.81; P = .0035).
 

Hematologic Malignancies


Zanubrutinib for Previously Treated Mantle Cell Lymphoma
The FDA granted an accelerated approval to the zanubrutinib (Brukinsa) in November 2019 for the treatment of adult patients with mantle cell lymphoma who have previously received at least 1 prior line of therapy. According to data from clinical trials, the BTK inhibitor led to tumor shrinkage in 84% of patients. This approval provides access to another therapeutic option for those patients whose disease relapses or becomes refractory to frontline therapy.

Fedratinib for Primary or Secondary Myelofibrosis
In August 2019, the FDA granted approval to fedratinib (Inrebic) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis (MF), including post-polycythemia vera or post-essential thrombocytopenia MF. This was the first approval in almost a decade for patients with MF. The decision was based on data from both clinical trials, JAKARTA and JAKARTA2, which evaluated the JAK2 inhibitor in 608 patients.

Ivosidenib for IDH1-Mutant Acute Myeloid Leukemia
Ivosidenib (Tibsovo) monotherapy was approved by the FDA in May 2019 for the treatment of adult patients with IDH1-mutant acute myeloid leukemia. The approval was based on data from a phase I trial, which demonstrated a 28.6% complete response (CR) rate and a 42.9% CR plus CR with partial hematologic recovery rate.

Selinexor for Heavily Pretreated Relapsed/Refractory Multiple Myeloma
In July 2019, the FDA granted an accelerated approval to selinexor (Xpovio) in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have previously received at least 4 prior lines of therapy and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody. The decision was based on data from part 2 of the phase II STORM trial, despite the FDA’s Oncologic Drug Advisory Committee’s 8-to-5 vote against the approval in February 2019.

Daratumumab/Rd Combination for Transplant-Ineligible Myeloma
In June 2019, the FDA approved daratumumab (Darzalex) in combination with lenalidomide (Revlimid) and dexamethasone (Rd) for the frontline treatment of patients with multiple myeloma who are ineligible for autologous stem cell transplant (ASCT). This was the first of 2 daratumumab approvals for patients with myeloma in 2019. The decision for this approval was based on the phase III MAIA (MMY3008) trial, in which the regimen led to a 44% reduction in the risk of disease progression or death compared with Rd alone.

Daratumumab Plus VTD for Newly Diagnosed Multiple Myeloma
The combination of daratumumab plus bortezomib (Velcade), thalidomide, and dexamethasone (VTD) was approved in September 2019 for the treatment of patients with newly diagnosed multiple myeloma who are eligible for ASCT. Based on data from part 1 of the phase III CASSIOPEIA trial, daratumumab plus VTD induced an improvement in the stringent CR rate, which was 28.9% in the investigational arm versus 20.3% with VTD alone. The trial is the first to show a clinical benefit for the combination of daratumumab and standard of care in this patient population.
 

Lung Cancer


“One of the most important FDA approvals of 2019 [for thoracic oncology] was the approval of atezolizumab in combination with carboplatin plus etoposide for extensive-stage small cell lung cancer [ES-SCLC],” Justin F. Gainor, MD, director of Targeted Immunotherapy at Massachusetts General Hospital and assistant professor of Medicine at Harvard Medical School in Boston, told Targeted Oncology. “We have not seen an advance in SCLC in decades. This is the first example of where we are seeing a significant improvement in OS, and that instantly changed the standard of care for these patients.”

Atezolizumab Regimen for Extensive-Stage Small Cell Lung Cancer
In March 2019, the FDA approved the combination of atezolizumab plus carboplatin and etoposide as frontline treatment of patients with ES-SCLC. The approval was based on data from the phase III Impower133 trial, which led to an improved median OS of 12.3 months versus 10.3 months with the combination of carboplatin plus etoposide and placebo.

Pembrolizumab for Metastatic Small Cell Lung Cancer
The FDA granted an accelerated approval to pembrolizumab in June 2019, for the treatment of patients with metastatic SCLC who experienced disease progressed on or after a platinum-based chemotherapy and at least 1 other prior line of therapy. The decision was based on data from both the KEYNOTE-158 Cohort G and KEYNOTE-028 Cohort C1. These findings demonstrated a 19% overall response rate (ORR), which included a 2% CR rate and a 17% partial response (PR) rate.

Atezolizumab Combination for Metastatic Nonsquamous Non–Small Cell Lung Cancer
In December 2019, the FDA granted approval to the combination of atezolizumab plus carboplatin and nab-paclitaxel (Abraxane) for the treatment of patients with metastatic nonsquamous non–small cell lung cancer. In the IMpower130 study, for which the approval was based, the median OS was 18.6 months with the regimen versus 13.9 months in patients treated with chemotherapy alone.
 

Breast Cancer


“Checkpoint blockade was approved for breast cancer for the first time in 2019. Specifically, the FDA granted accelerated approval to the PD-L1 checkpoint inhibitor atezolizumab (Tecentriq),” Peter P. Lee, MD, chair of the Department of Immuno-Oncology at City of Hope, told Targeted Oncology. “This was a significant approval because up until that time, none of the immunotherapy treatments had worked well or had been approved for breast cancer, the most common cancer in women. This immunotherapy is approved to be used for advanced triple-negative breast cancer (TNBC), an aggressive breast cancer that comprises about 15% of all breast cancer cases.”

Atezolizumab Plus Nab-Paclitaxel for Triple-Negative Breast Cancer
The combination of atezolizumab plus nab-paclitaxel was approved by the FDA in March 2019 for the treatment of patients with unresectable locally advanced or metastatic PD-L1–positive TNBC. This approval was based on data from the phase III IMpassion130 trial, which showed a reduced risk of progression or death by 40% with the combination versus nab-paclitaxel alone. This marks the first approval of an immunotherapy in this patient population.

Alpelisib for PIK3CA-Mutated Breast Cancer
In May 2019, alpelisib (Piqray) was approved by the FDA for the treatment of postmenopausal women and men with HR-positive, HER2-negative, PI3KCA-mutant advanced or metastatic breast cancer following progression on or after endocrine-based therapy. Alpelisib is the first PI3K inhibitor to demonstrate benefit in this patient population. According to findings from the phase III SOLAR-1 trial, the targeted agent induced a median PFS of 11.0 months in patients with PIK3CA mutations compared with 5.7 months with placebo plus fulvestrant (HR, 0.48; 95% CI, 0.32-0.71).
 

Genitourinary Cancers


Pembrolizumab Plus Axitinib for Advanced Renal Cell Carcinoma
In April 2019, the combination of pembrolizumab plus axitinib (Inlyta) was approved by the FDA for the frontline treatment of patients with advanced renal cell carcinoma, based on data from the phase III KEYNOTE-426 study. The trial demonstrated a statistically significant improvement in OS, PFS, and ORR. This is the first anti–PD-1 therapy approved as part of a combination regimen in this patient population.

Erdafitinib for Locally Advanced/Metastatic Bladder Cancer with FGFR3/2 Alterations
The FDA granted an accelerated approval to erdafitinib (Balversa) for the treatment of adult patients with locally advanced or metastatic bladder cancer with an FGFR3 or FGFR2 alteration who have progressed on platinum-based chemotherapy. This is the first targeted agent approved for the treatment of metastatic bladder cancer. Erdafitinib induced a 32.2% ORR, which included a 2.3% CR rate and a PR rate of nearly 30%.

Enzalutamide for Metastatic Castration-Sensitive Prostate Cancer
Enzalutamide (Xtandi) was approved by the FDA in April 2019 for the treatment of metastatic castration-sensitive prostate cancer. This is now the first oral drug to be approved for 3 different types of advanced prostate cancer. The approval was based on data from the phase III ARCHES trial, which demonstrated a 61% decrease in the risk of radiographic progression or death compared with placebo plus androgen deprivation therapy.
 

Other Oncology and FDA News


Pembrolizumab for Stage III Melanoma
In February 2019, the FDA granted approval to pembrolizumab as an adjuvant therapy for patients with high-risk stage III melanoma with lymph node involvement following complete resection. This is the first anti–PD-1 therapy to be evaluated in the adjuvant setting in patients with stage IIIA, IIIB, and IIIC melanoma. The approval was based on the phase III EORTC 1325/KEYNOTE-054 trial, which demonstrated a 43% reduction in the risk of disease recurrence or death compared with placebo.

Pembrolizumab Plus Lenvatinib for Advanced Endometrial Carcinoma
The FDA granted an accelerated approval to pembrolizumab in combination with lenvatinib (Lenvima) for the treatment of patients with advanced endometrial cancer who have disease progression following a prior systemic therapy. The indication is for patients who are not candidates for curative surgery or radiation and who have had disease that is not microsatellite instability–high or mismatch repair deficient.

“It’s highly likely that a number of new drugs will be FDA approved on the basis of genomically informed medicine. In particular, drugs that target a particular gene or pathway will be on the rise in 2020, both in clinical trials and moving toward FDA approval,” said Gruber. “Treatments that target genetic mutations or misspellings of a cancer gene are going to be approved this year. One of the leading examples is AMG 510. My colleague Marwan Fakih, MD, is involved in AMG 510’s clinical research that will hopefully garner FDA approval.”

AMG 510 received a fast track designation from the FDA in September 2019 for the treatment of patients with previously treated metastatic non–small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. This move came about after updated data were presented at the International Association for the Study of Lung Cancer 2019 World Conference on Lung Cancer from an ongoing phase I trial, which demonstrated that the agent had a disease control rate of 100% at the target dose in evaluable patients. This is the first investigational KRAS inhibitor to advance to the clinic.
 

Looking Ahead


As more targeted therapies become available and enter clinical trials, experts agree that genomic testing will play an important role in the development of cancer treatments in 2020 and beyond.

“Genomic testing of paired germline and tumor specimens to determine both the underlying etiology of why a person developed cancer and how to treat it will continue to grow in popularity for all cancer types,” Thomas Slavin, MD, a clinical geneticist at City of Hope, told Targeted Oncology. “At City of Hope, we will be leading this charge with TGen and other partnerships. This will be a very important step toward driving the use of genomics in oncology to help patients and their families.”

Another expert, Russell Rockne, PhD, director of the Division of Mathematical Oncology at City of Hope, added, “I predict that mathematics and computational biology will continue to increase its influence and role in basic and translational research in cancer. This is driven by the amount and complexity of data that is being routinely collected: from genomics to imaging to the electronic health record. Informatics and data science have mathematics as a core methodology.”

Incidences of cardiovascular and pancreatic dysfunction, such as heart disease and diabetes, continue to appear to be associated with a diagnosis of cancer and treatments, according to Joshua Tompkins, PhD, assistant research professor at the City of Hope. Insights into disease-specific biomarkers could aid in identifying patients that are more vulnerable to the complications of cancer treatment, which could result in identifying new strategies to protect patient’s health during treatment.
 
“Recent expansions in DNA sequencing technologies have enabled the sequencing of hundreds of thousands of human genomes and identified critical DNA mutations, breaks, and translocations associated with specific cancer types,” Tompkins said. “New, affordable DNA sequencers include portable, handheld devices with the capacity to sequence long DNA reads and provide information on DNA chemical modification and accessibilities (i.e. nanopore sequencers). This is particularly important as individuals possess 1 genome, but an endless array of epigenomes, which change over development and aging, across tissue types, and during cancer development and progression.”

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