Six indications for immune checkpoint inhibitors (ICIs) granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) will hold a special 3-day public hearing on April 27 to 29 to allow expert commentary and patient testimony about the drugs, which are being used to treat triple-negative breast cancer (TNBC), metastatic urothelial carcinoma (mUC), gastric cancers, and hepatocellular carcinoma (HCC), the agency said Thursday. Based on the testimony, ODAC will consider whether the approvals should be withdrawn and whether additional trials should be conducted.1

The hearings will involve 2 indications for atezolizumab (Tecentriq), 3 for pembrolizumab (Keytruda), and 1 for nivolumab (Opdivo). Specifically, these indications will be reviewed:

Atezolizumab―in combination with nab-paclitaxel (Abraxane) for the treatment of patients with PD-L1–positive unresectable locally advanced or metastatic TNBC; and as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy

Pembrolizumab—as monotherapy for patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy; for patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma that express PD-L1 and has progressed after 2 or more prior lines of therapy; and for patients with HCC previously treated with sorafenib (Nexavar)

Nivolumab—as a single agent for patients with HCC who previously received sorafenib

The FDA announced the hearings after a flurry of ICI indications were voluntarily withdrawn by pharmaceutical companies, starting in December 2020, as part of what the FDA described as an industry-wide evaluation of accelerated approvals in oncology “in which confirmatory trials did not confirm clinical benefit.”1

As part of the voluntary withdrawals, Bristol Myers Squibb and Merck said they will discontinue indications for nivolumab and pembrolizumab, respectively, for patients with metastatic small cell lung cancer whose disease has progressed after platinum-based chemotherapy and at least 1 other line of therapy; AstraZeneca will withdraw an indication for durvalumab (Imfinzi) for patients with locally advanced or mUC that has progressed after chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy; and Genentech will halt an indication for atezolizumab for patients with mUC previously treated with platinum-based chemotherapy.

Under the accelerated approval program, drugs are able to gain indications more quickly than through a regular approval timeline based on a surrogate end point. Pharmaceutical companies are then required to conduct a trial that confirms a clinical benefit; if the study is successful, the FDA grants regular approval status.2

The FDA’s Oncology Center of Excellence, which reviews and expedites the development of cancer drugs, requested the April hearings. The center is headed by Richard Pazdur, MD, a 2019 Giants of Cancer Care® award winner for Community Outreach who also is serving as acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” Pazdur said in a statement.1 “The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn.”

The hearings will give oncology experts outside of the FDA and patients with cancer an opportunity to describe their experiences with the drugs, said Pazdur. “After this advisory meeting, our staff will consider the committee’s comments and will make final decisions regarding continuing approval of each indication,” he said.

The accelerated approval pathway, introduced in 1992, has been “an extremely important mechanism to promote development of and access to therapies for serious or life-threatening illnesses,” according to a report by Friends of Cancer Research. Cancer therapies approved through the pathway reached patients a median of 3.4 years earlier than they would have if their status was dependent upon a primary clinical end point such as overall survival for approval, the report noted.3

Since the program began, only 6% of accelerated approvals for oncology drugs have been withdrawn, including the 4 recent ICI indications, the FDA said.1

Other indications for the ICIs under review are not affected by the April hearings or the announced withdrawals.

FDA in brief: FDA Oncologic Drugs Advisory Committee to review status of six indications granted accelerated approval. FDA. March 11, 2021. Accessed March 11, 2021. 

Accelerated approval program. FDA. Updated October 26, 2020. Accessed March 11, 2021. 

Optimizing the use of accelerated approval. Friends of Cancer Research; 2020. Accessed March 11, 2021. https://bit.ly/38vV28l

This article was originally published on OncLive as, "

FDA Will Reassess 6 Immunotherapy Accelerated Approvals

Articles

Six indications for immune checkpoint inhibitors granted under the FDA’s accelerated approval process that later failed confirmatory clinical trials are being reassessed as the agency continues an industry-wide evaluation of the pathway.

FDA to Reassess Accelerated Immunotherapy Approvals

Warnings and Precautions added: keratitis

Keratitis reported in 0.7% (n = 6) of 833 patients treated with osimertinib in clinical trials.

Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist.

Adverse Reactions updated: AURA3 clinical trial experience:

Serious adverse reactions were reported in 18% of patients treated with osimertinib and 26% in the chemotherapy group.

No single serious adverse reaction was reported in 2% or more patients treated with osimertinib. One patient (0.4%) treated with osimertinib experienced a fatal adverse reaction (interstitial lung disease/pneumonitis).

AURA3 was not designed to demonstrate a statistically significant reduction in adverse reaction rates for osimertinib.

Warnings and Precautions added: benzyl alcohol preservative

Serious and fatal adverse reactions including gasping syndrome can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including blinatumomab (with preservative).

Gasping syndrome is characterized by central nervous syndrome depression, metabolic acidosis, and gasping respirations.

When prescribing blinatumomab (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources.

Blinatumomab (with preservative) contains 7.4 mg of benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.

Warnings and Precautions added: respiratory disorders

Interstitial pneumonia/pneumonitis, interstitial lung disease, and acute respiratory distress syndrome have been reported and may be associated with fatal outcome.

Patients with underlying lung disease may be at higher risk for these events.

Acute respiratory distress syndrome may occur in the setting of infection.

Interrupt cabazitaxel if new or worsening pulmonary symptoms develop.

Patient Information added: lung or breathing problems

Patients should be advised that lung or breathing problems may develop with cabazitaxel and may lead to death.

People who have lung disease before receiving cabazitaxel may have a higher risk for developing lung or breathing problems with cabazitaxel treatment.

Warnings and Precautions expanded and updated

Pembrolizumab can cause severe or life-threatening infusion-related

reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients receiving pembrolizumab.

Pembrolizumab can cause immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, thyroid disorders, type I diabetes mellitus, nephritis, and thyroiditis

Other clinically important immune-mediated reactions may involve any organ system.

An update on the labeling changes from the FDA.

August Adverse Events Report: FDA Labeling Changes

Embryo-fetal toxicity: Advise females of reproductive potential to use effective contraceptive measures to prevent pregnancy while being treated with bosutinib and for at least 30 days after the final dose.

Skin and subcutaneous tissue disorders (postmarketing experience): Stevens-Johnson syndrome

Musculoskeletal and connective tissue disorders (postmarketing experience): musculoskeletal pain upon treatment discontinuation, including myalgia, pain in extremities, arthralgia, bone pain.

Infections (postmarketing experience): hepatitis B virus reactivation

Acute lymphoblastic leukemia: Superficial edema was a common finding in all studies and was described primarily as periorbital or lower limb edemas. These edemas were reported as grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures or, in some patients, by reducing the dose of imatinib.

Skin and subcutaneous tissue disorders: nail disorders including paronychia; severe cutaneous adverse skin reactions, including Stevens-Johnson syndrome and toxic epidural necrolysis.

Cardiac disorders: ventricular arrhythmias/Torsades de Pointes, electrocardiogram QT prolongation.

Severe skin reactions: lapatinib may cause severe skin reactions. Advise patients to inform their healthcare provider immediately if symptoms develop, including skin rash; red skin; blistering of the lips, eyes, or mouth; peeling of the skin; fever; or any combination of these.

CYP3A4 inhibitors: Vemurafenib is a substrate of CYP3A4; therefore, coadministration of strong CYP3A4 inhibitors may increase vemurafenib plasma concentrations and may lead to increased toxicity.

CYP3A4 inducers: Coadministration of vemurafenib with rifampin, a strong CYP-3A4 inducer, decreased vemurafenib plasma concentrations and may result in decreased efficacy. Avoid coadministration of vemurafenib with strong CYP3A4 in- ducers (eg, phenytoin, carbamazepine, rifampin), and replace these drugs with alternative drugs when possible. If coadministration of a strong CYP3A4 inducer is unavoidable, increase the dose of vemurafenib by 240 mg (1 tablet) as tolerated.

Females of reproductive potential: Based on its mechanism of action, vemurafenib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with vemurafenib and for 2 weeks after the final dose.

Risk summary: There are no available data on the use of vemurafenib in pregnant women to determine the drug-associated risk; however, placental transfer of vemurafenib to a fetus has been reported.

FDA labeling changes reflecting adverse events.

June Adverse Events Report: FDA Labeling Changes

The addition of pertuzumab (Perjeta) to standard postoperative trastuzumab (Herceptin) therapy for patients with HER2-positive early breast cancer slightly improved the rate of recurrence overall but had a greater benefit for individuals with higher-risk disease, particularly as more time elapsed, according to early results from the phase III APHINITY trial.

The findings suggest that the dual HER2 targeting strategy in early-stage adjuvant settings should be stratified by risk level, experts said while discussing the results at the 2017 ASCO Annual Meeting.

The APHINITY findings demonstrated that patients who received adjuvant pertuzumab along with trastuzumab plus chemotherapy had an invasive disease-free survival (IDFS) rate of 94.1% after 3 years’ follow-up versus 93.2% for those who received trastuzumab plus chemotherapy and placebo (HR, 0.82; 95% CI, 0.67-1.00). In all, 4805 patients participated in the study.

The benefit was more pronounced among higher-risk subgroups, with the curve widening over time. After a follow-up of 4 years, the IDFS rate for patients with node-positive disease was 89.9% with pertuzumab versus 86.7% with standard therapy (HR, 0.77; 95% CI, 0.62-0.96; 

 = .019). For participants with hormone receptor (HR)—negative disease, the IDFS rate with pertuzumab was 91.0% after 4 years compared with 88.7% in the control group (HR, 0.76; 95% CI, 0.56-1.04;

“These are very early results, but given that the absolute benefit from adding pertuzumab was modest, we should consider using it primarily in women with the highest risk—those with node-positive and hormone receptor-negative breast cancer,” said lead study author Gunter von Minckwitz, MD, PhD, said in a statement.

Von Minckwitz, who is president of the German Breast Group in Neu-Isenburg, Germany, said the study met its primary endpoint by exceeding a preset threshold for reducing the risk of an IDFS event. He said the pertuzumab-containing regimen reduced the risk of developing invasive breast cancer by 19%. After a median follow-up of 45.4 months, 7.1% (n = 171) in the pertuzumab group had developed invasive breast cancer, compared with 8.7% (n = 210) in the standard therapy group (HR, 0.81; 95% CI, 0.66-1.00; 

The number of patients needed to treat to achieve benefit was 112 for the study overall, 63 in the HR-negative subgroup, and 56 in the node-positive subgroup.

The APHINITY trial results represent “a step forward in the treatment of HER2-positive breast cancer,” said ASCO expert Harold J. Burstein, MD, PhD, FASCO, during a presscast on June 5, where the findings were discussed. “The relatively narrow benefits in numerical terms that you are seeing reflect the overall good prognosis.”

Burstein, an associate professor at the Dana-Farber Cancer Institute, said the prognosis for HER2-positive breast cancer had evolved “from worst to first” in the 12 years since adjuvant trastuzumab was first shown to improve disease-free survival for patients with HER2-positive breast cancer. “Because of that success, when you look at data from studies like the APHINITY trial, the boats have been raised very high.”

In translating the potential for the dual HER2 regimen into clinical practice in early breast cancer, Burstein said the strategy seems most beneficial in the subgroups where it showed more activity but not for patients with stage I disease where the risk of recurrence is less than 5%.

“In the management of HER2-positive breast cancer, we really are seeing 2 diverging strands,” Burstein said. “For low-risk, particularly stage I tumors, there’s a lot of talk about de-escalating regimens, finding biologically driven regimens, and sparing patients longer durations of treatment or extra medicines and, on the other extreme for higher-risk cases, demonstrating that additional anti-HER2 therapy will help lower the risk of recurrence.”

Pertuzumab and trastuzumab are monoclonal antibodies that target HER2 activity by different mechanisms of action. Pertuzumab targets the HER2 dimerization domain, blocking its interaction with other HER family members including EGFR, HER3, and HER4, while trastuzumab inhibits proliferation of HER2-overexpressing tumor cells.

The FDA has approved pertuzumab in combination with trastuzumab and docetaxel as neoadjuvant therapy for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (>2 cm or node positive). The combination also is approved for HER2-positive metastatic disease.

The APHINITY trial sought to determine whether the addition of pertuzumab would improve outcomes in the adjuvant setting. The study recruited patients with T1-3 HER2-positive early breast cancer who had undergone mastectomy or lumpectomy. Overall, 63% of the participants had node-positive disease, and 36% had HR-negative disease.

Participants were randomized to receive adjuvant chemotherapy for 18 weeks and 1 year of either pertuzumab plus trastuzumab (n = 2400) or trastuzumab plus placebo (n = 2405). A choice between several standard anthracycline-taxane sequences or a nonanthracylcine (TCH) regimen was permitted. Additionally, patients could receive radiotherapy and/or endocrine therapy after the end of adjuvant chemotherapy.

Von Minckwitz said the addition of pertuzumab did not significantly increase cardiotoxicity, which can be a worrisome adverse event with anti-HER2 therapy. The primary cardiac endpoint was heart failure, defined as New York Heart Association class III/IV failure plus a drop in left ventricular ejection fraction (≥10% from baseline and to <50%). Heart failure was reported in 17 patients (0.7%) in the pertuzumab-containing arm versus 8 participants in the standard therapy group (0.3%). Approximately half of the patients in each group recovered, and there were 2 cardiac deaths in each arm.

Diarrhea of grade ≥3 severity was more common with the pertuzumab-containing therapy, affecting 9.8% of patients in the safety analysis versus 3.7% of those who received standard therapy. Von Minckwitz said the incidence of diarrhea occurred predominantly during chemotherapy and more frequently among patients who were administered TCH.

The APHINITY study was funded by Hoffmann-La Roche Ltd, which is developing pertuzumab and trastuzumab along with Genentech, a member of the Roche Group.

von Minckwitz G, Procter MJ, De Azambuja E, et al. APHINITY trial (BIG 4-11): A randomized comparison of chemotherapy (C) plus trastuzumab (T) plus placebo (Pla) versus chemotherapy plus trastuzumab (T) plus pertuzumab (P) as adjuvant therapy in patients (pts) with HER2-positive early breast cancer (EBC). 

Adjuvant pertuzumab may help some early breast cancer patients.

Adding Pertuzumab to Trastuzumab Shows Benefits in Early HER2-Positive Breast Cancer

Newly diagnosed patients with cancer experienced improvements in quality of life and lower levels of distress by participating in a web-based stress management program, according to results of a study presented at the 2017 ASCO Annual Meeting.

The randomized study demonstrated that most of the participants reported feeling distressed at baseline and that a structured online program guided by psychologists was an effective method of offering them assistance, researchers said when discussing the findings during a presscast in advance of the presentation.

“Our online stress management program was feasible with newly diagnosed cancer patients during active treatment,” said lead study author Viviane Hess, MD, a medical oncologist at the University Hospital of Basel in Switzerland. “We were able to reach cancer patients via the Internet. At baseline, 3 of 4 patients were highly distressed, so we reached a target population in need of support.”

Hess said most patients who receive a cancer diagnosis experience a “high level of distress,” but do not have access to psychological support. She said studies in patients without cancer have shown that web-based, therapist-guided interventions can be as effective in helping individuals cope with mental disorders such as anxiety and depression.

In order to meet such needs, oncologists and psychologists designed the STREAM program as an intervention that covers 8 weekly topics such as bodily reaction to stress, cognitive stress reduction, feelings, and social interactions. For each topic, participants receive written and audio information and complete exercises and questionnaires. Psychologists review patients’ feedback on a weekly basis and offer written guidance and support through a secure online portal; patients can then respond in writing.

To test the STREAM program, 129 patients newly diagnosed with cancer were randomized within 12 weeks of starting anticancer treatment to an immediate intervention (n = 64) or to a control group who would have access to the program after a 2-month period (n = 65). The psychologists were based in Basel, but the patients were living in Germany, Switzerland, and Austria.

Overall, the median age of the participants was 52 years (range, 46-58) and 84.5% were female. The cancer diagnoses covered approximately 10 tumor types; more than 70% had breast cancer while 8.5% had lymphoma, 5.4% each had gynecological or gastrointestinal tract cancers, 3.9% had lung cancer, 3.1% had central nervous system or head and neck cancer, 2% had urogenital tract cancer, and 0.8% had skin or soft tissue cancer. Eighty-six percent had localized disease while 14% had metastatic disease.

To evaluate the program, investigators measured quality of life including fatigue using the Functional Assessment in Cancer Therapy-Fatigue (FACIT-F) scale, psychological distress with Psychological distress on the Distress Thermometer (DT), and anxiety and depression with the Hospital Anxiety and Depression Scale (HADS).

Investigators found that patients who participated in the intervention program experienced significantly improved quality of life with FACIT-F scores that were an average of 8.59 points higher (range, 2.45-14.73; 

 = .007). Similarly, those who received the intervention had a greater improvement in their distress levels, with an average 0.85 decline on the DT scale (range, -1.60 to -0.10; 

 = .03). Anxiety and depression as measured by the HADS score also declined for the intervention group by 1.28 points (range, -3.02 to 0.45) but this difference was not statistically significant (

Hess said the findings support the use of remote technologies. “I think online psychological support will be much more important in the years to come, as the digital generation reaches the age when they are at higher risk of cancer. For them, it will be natural to use such online tools and communicate without face-to-face interaction, and so now is the time to standardize and validate the tools,” Hess said in a press release.

Researchers plan to translate the STREAM program, which is currently available only in German, into other languages.

Commenting on the research, ASCO expert Don S. Dizon, MD, FACP, said the study demonstrated the value of psychological support after therapy starts. He said most oncologists assume patients will experience distress when initially diagnosed but that such feelings would abate as they undergo curative therapy.

“Trying to get these patients support can be an issue because they’re at cancer centers quite frequently for medical therapy,” he said. “Trying to squeeze psychological expertise into their treatment plans can become difficult. Utilizing an online system not only has been shown to be feasible, but the promise of being effective as well is quite grounded now in an evidence-based randomized trial.”

Hess V, Grossert A, Alder J, et al. Web-based stress management for newly diagnosed cancer patients (STREAM): A randomized, wait-list controlled intervention study.

Patients new diagnosed with cancer were able to improve quality of life and distress by through a web-based stress management program.

Newly Diagnosed Patients Better Manage Stress With Web-Based STREAM Therapy

Earlier intervention with abiraterone acetate (Zytiga) lowered the risk of death by nearly 40% for men with high-risk advanced or metastatic prostate cancer who were newly diagnosed or had not yet received hormone therapy in findings from 2 clinical trials presented at the 2017 ASCO Annual Meeting.

Experts said results from the LATITUDE and STAMPEDE trials would immediately change clinical practice.

Results from the phase III LATITUDE trial demonstrated that the addition of abiraterone plus prednisone to androgen deprivation therapy (ADT) lowered the risk of death by 38%. The combination more than doubled median progression-free survival (PFS) to 33 months compared with 14.8 months for ADT plus placebo in men with newly diagnosed, high-risk metastatic disease (HR, 0.47; 95% CI, 0.39-0.55; 

In the STAMPEDE trial, which consisted of a broader population of high-risk hormone-naïve patients including some participants with nonmetastatic disease, results showed that the addition of abiraterone to standard initial therapy lowered the relative risk of death by 37% and improved the PFS by 71%.

 The 3-year survival rate was 83% with abiraterone plus standard therapy compared with 76% for standard therapy alone.

“It is remarkable to see the similarity in survival benefit across the 2 studies in the metastatic population,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope in Duarte, California, who served as ASCO’s expert commentator during the presscast Saturday where both studies were discussed.

He said the LATITUDE data “should immediately reshape our treatment algorithms for prostate cancer, and abiraterone with conventional hormone therapy should become a new standard of care for men with high-risk metastatic prostate cancer.” He said the STAMPEDE data confirm that approach for metastatic patients but that more study is needed to move abiraterone forward for individuals with nonmetastatic disease.

However, Nicholas James, BSc, MBBS, PhD, lead investigator on the STAMPEDE trial, said abiraterone plus prednisone improves the standard of care for men with hormone-naïve prostate cancer regardless of metastatic disease status.

“Based on the magnitude of clinical benefit, we believe that the upfront care for patients newly diagnosed with advanced prostate cancer should change,” James said in a statement.

The evidence in favor of earlier treatment for patients with advanced or metastatic prostate cancer has been an emerging development in recent years, experts noted at the press conference. In 2014, results from the randomized phase III CHAARTED study involving 790 men demonstrated that the addition of docetaxel to ADT prolonged median overall survival (OS) for men with newly diagnosed metastatic, hormone-sensitive prostate cancer by nearly 14 months compared with ADT alone.

In 2015, a noteworthy benefit was observed in another part of the STAMPEDE study, which is an ongoing multiarm, multistage randomized clinical trial being conducted in the United Kingdom and Switzerland. The much larger trial, which involved 2962 patients, demonstrated a median OS of approximately 77 months for patients receiving docetaxel plus standard therapy versus 67 months for standard therapy alone in men with newly diagnosed, hormone-naïve advanced prostate cancer.

Although docetaxel improves outcomes, toxicities associated with the chemotherapy agent are a concern, particularly for older patients who are more likely to develop metastatic prostate cancer, noted Pal. He said abiraterone “provides an important alternative to the use of chemotherapy.”

Abiraterone has been approved by the FDA since 2011 in combination with prednisone for patients with metastatic castration-resistant prostate cancer. The drug, which is orally administered, blocks androgen production by inhibiting CYP17, an enzyme expressed in testicular, adrenal, and prostate tumor tissue.

“The benefit from early use of abiraterone we saw in this study is at least comparable to the benefit from docetaxel chemotherapy which was observed in prior clinical trials, but abiraterone is much easier to tolerate, with many patients reporting no side effects at all,” said Karim Fizazi MD, PhD, lead author of the LATITUDE study, in a statement.

The next step for the research would be to determine whether adding abiraterone to docetaxel and ADT further improves outcomes, said Fizazi, who is head of the department of cancer medicine at Gustave Roussy, University Paris-Sud in Villejuif, France.

The multinational LATITUDE trial enrolled men who had not previously received ADT therapy and had at least 2 of 3 risk factors: Gleason score greater than or equal to 8, measurable visceral metastases, or 3 or more bone lesions. Results presented at the conference were from the first interim analysis involving 1199 patients: 597 in the abiraterone arm and 602 in the control group.

Patients with newly diagnosed metastatic disease live less than 5 years on average, Fizazi said. He said this category includes 3% to 5% of patients in the United States and other Western countries, and rises as high as approximately 60% of newly diagnosed patients in some Asian countries.

The co-primary endpoints for the study were OS and radiographic PFS. Based on results thus far, the International Data Monitoring Committee has unanimously recommended unblinding the study and allowing patients to cross over to the abiraterone arm.

After a median follow-up of 30.4 months, the median overall survival (OS) had not yet been reached (NR) in the abiraterone arm; the median OS in the control group was 34.7 months (HR, 0.62; 95% CI, 0.51-0.76; 

 <.0001). The OS rate at 3 years was 66% in the abiraterone group versus 49% with placebo.

The abiraterone-containing regimen also has been shown to significantly improve secondary endpoints compared with the control group in the time to pain progression (NR vs 16.6 months), prostate-specific antigen (PSA) progression (33.2 vs 7.4 months), chemotherapy (NR vs 38.9 months), and subsequent prostate cancer therapy (NR vs 21.6 months). The hazard ratios for those endpoints ranged from 0.30 for PSA progression to 0.70 for pain progression in favor of the abiraterone arm, with P <.0001. The time to symptomatic skeletal-related events was not reached in both arms.

In terms of toxicities, the abiraterone-containing regimen resulted in higher rates of grade 3/4 adverse events compared with the control arm including hypertension (20.3% vs 10.0%); hypokalemia (10.4% vs 1.3%); elevated alanine aminotransferase (5.5% vs 1.3%), and elevated aspartate aminotransferase (4.4% vs 1.5%).

“We need to be cautious when using abiraterone in men who have an increased risk for heart problems, such as those with diabetes,” said Fizazi.

The STAMPEDE trial is the largest study of first-line abiraterone ever conducted in patients with locally advanced or metastatic prostate therapy. In all, 1917 patients were randomized 1:1 to receive either abiraterone at 1000 mg daily plus prednisone at 5 mg daily plus standard of care (SOC) versus SOC alone. SOC consisted of ADT for at least 2 years with radiotherapy required for participants with N0M0 disease and encouraged for those with stage N+M0.

Treatment duration depended on stage and intent to administer radiotherapy: patients not receiving radiotherapy or with M1 disease were eligible to continue treatment until radiological, clinical, or prostate-specific antigen (PSA) progression. Other patients continued therapy at least 2 years or until progression.

The median age of participants was 67 years (range, 39-85 years); 52% had prostate cancer that had spread, of whom 88% had disease that spread to the bone; and 95% were newly diagnosed.

At a median follow up of 40 months, 184 deaths had occurred in the abiraterone group and 262 deaths in the standard therapy arm. The median adjusted HR for the median OS was 0.63 (95% CI, 0.52-0.76; 

 = .0000012). Abiraterone-containing therapy also markedly improved skeletal-related outcomes with a 55% reduction in the time for such problems to develop (HR, O.45; 95% CI, 0.36-0.38).

Although most adverse events (AEs) were similar between the 2 groups, researchers reported that serious AEs occurred more frequently among participants who received abiraterone, with 41% of patients reporting grade 3/4 AEs compared with 29% in the standard therapy group.

As with the LATITUDE trial, the main AEs occurring more frequently with abiraterone were cardiovascular problems such as high blood pressure; there were also more liver problems. There were 2 treatment-related deaths in the abiraterone group and in the standard therapy group, researchers reported.

Fizaxi K, Tran N, Fein LE, et al; the LATITUDE investigators. LATITUDE: A phase 3 double-blind, randomized trial of androgen deprivation therapy (ADT) with abiraterone acetate (AA) plus prednisone (P) or placebos (PBOs) in newly diagnosed high-risk metastatic hormone-naïve prostate cancer (mHNPC) patients (pts). 

James ND, DeBono JS, Spears MR, et al. Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE (NCT00268476). 

Sweeney C, Chen Y-H, Carducci MA, et al. Impact on OS with chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic prostate cancer: an ECOG-led phase III randomized trial. 

James ND, Sydes, MR, Mason, MD, et al. Docetaxel and/or zoledronic acid for hormone-naïve prostate cancer: First overall survival results from STAMPEDE. 

According to findings presented at the 2017 ASCO Annual Meeting, earlier intervention with abiraterone acetate (Zytiga) lowered the risk of death by 40% for men with high-risk advanced or metastatic prostate cancer.

Abiraterone Lowers Risk of Death from Prostate Cancer in Two Clinical Trials

Most patients with low-risk advanced colon cancer would benefit from a 50% reduction in the oxaliplatin-containing chemotherapy they typically receive after surgery without notably increasing their risk of recurrence and while markedly decreasing the likelihood that they will develop neuropathy, according to an analysis that challenges the current standard of care and paves the way for a more personalized approach.

The results of the IDEA international collaboration, which involved more than 12,800 patients, demonstrated that a 3-month course of adjuvant chemotherapy is nearly as effective as the standard 6-month course for patients with stage IIIC, lymph-node positive, colon cancer who have undergone surgery, according to findings presented at the 2017 ASCO Annual Meeting.

Overall, the 3-month regimen was associated with a less than 1% lower risk of recurrence compared with a 6-month course as measured by the 3-year disease-free survival (DFS) rate (74.6% vs. 75.5%, respectively). In a subset of patients categorized as low risk of cancer recurrence, defined as cancer spread to 1 to 3 lymph nodes and not completely through the bowel wall, there was almost no DFS difference between a 3-month versus 6-month course of therapy (83.1% vs 83.3%).

Additionally, the rates of grade ≥2 neurotoxicity were approximately 30% less with the shorter duration of chemotherapy.

The findings will change the standard of care for 60% of patients with low-risk colon cancer, which accounts for about 20,000 patients annually in the United States and approximately 400,000 individuals worldwide, said senior study author Axel Grothey, MD, an oncologist at the Mayo Clinic Cancer Center in Rochester, Minnesota, who discussed the results during an ASCO presscast June 4.

For higher risk patients, the analysis provides a framework for clinicians to discuss balancing risks versus benefits, Grothey said. “We come into clinical judgment,” he said. “How much are we willing to push patients into 6 months of therapy for a very small minimal difference in disease-free survival?”

Since 2004, adjuvant therapy for this population has consisted of oxaliplatin-containing chemotherapy administered over 6 months. In the study, investigators examined pooled results for patients who had received either FOLFOX (leucovorin, fluorouracil, oxaliplatin) or CAPOX (capecitabine, oxaliplatin), which also is known as XELOX.

Although these regimens have improved survival for patients, oxaliplatin is associated with cumulative dose—dependent nerve damage, such as numbness, tingling, and pain that many patients find debilitating and that can persist long after therapy ends, sometimes permanently. Grothey said dose reductions and early discontinuation due to neurotoxicity are common.

The IDEA investigators reached a consensus on a risk-based approach to adjuvant chemotherapy for patients with stage III colon cancer: for patients with T1-3 N1 disease, they recommended 3 months of chemotherapy; for patients with T4 and/or N2 or other high-risk factors, they advise determining the duration of therapy by tolerability, patient preference, assessment of risk recurrence factors, and choice of regimen.

“This is a great day for patients throughout the world,” said Nancy Baxter, MD, FRCSC, PhD, chief of the General Surgery Department at St. Michael’s Hospital in Toronto, Canada, who served as ASCO’s expert commentator during the presscast. “What we’ve heard today is practice-changing work that shows for most people with stage III colon cancer, 3 months of treatment provides all the benefits of 6 months of treatment with fewer risks. Less is more.”

The study synthesized data from 6 phase III trials concurrently conducted in 12 countries in North America, Europe, and Asia through IDEA, the International Duration Evaluation of Adjuvant therapy collaboration. “It’s by far the largest prospective study conducted in the history of colorectal cancer research,” said Grothey.

Patients were randomized according to duration of therapy (3 months vs 6 months); regimens were not compared with each other. Only FOLFOX was administered in the United States, where patients participated through the Alliance/SWOG 80702 trial. Sixty-percent of the participants received FOLFOX, and 40% received CAPOX.

Of the participants in the trials with stage IIIC T1-4 colon cancer, 13% had T1-2 disease, 66% had T3, and 21% had T4. Approximately 60% had low-risk disease (T-1 N1) and 40% had high-risk (T4 or N2). The median follow-up was 39 months.The goal of the study was to determine whether 3 months of adjuvant chemotherapy would be as effective as 6 months. Grothey said patients and oncologists agreed in the planning of the studies that a shorter duration of therapy, “should not sacrifice more than 12% of the benefit of adjuvant therapy.” In statistical terms, that meant that the upper limit of the 95% confidence interval (CI) for the DFS hazard ratio (HR) should not exceed 1.12.

Under that definition, the DFS findings for the overall patient population favored the 3-month regimen but did not meet the threshold for statistically significant noninferiority (HR, 1.07; 95% CI, 1.00-1.15). When analyzed by the type of regimen, the findings in favor of a 3-month duration were statistically significant for CAPOX (HR, 0.95; 95% CI, 0.85-1.06), but not for FOLFOX (HR, 1.16; 95% CI, 1.06-1.26).

In terms of risk groups, the DFS was 0.2% lower with a 3-month versus 6-month regimen among low-risk patients (83.1% vs 83.3%) but 1.7% lower among high-risk patients (62.7% vs 64.4%). When analyzed by regimen, the DFS was 2.4% lower when FOLFOX was administered in a shorter versus longer regimen (73.6% vs 76.0%) but 1.1% higher with CAPOX (75.9% vs 74.8%).

However, the rates of grade ≥2 neurotoxicity were statistically significantly lower (P <.0001) for patients who received 3 months rather than 6 months of chemotherapy, regardless of the regimen: 17% versus 48% for FOLFOX and 15% versus 45% for CAPOX.

Grothey pointed out that the IDEA research was funded through the National Institutes of Health (NIH), public agencies in other countries, and philanthropies. He noted that commercial companies do not focus on shortening therapy.

“This type of work can only be done with federal funding,” agreed Baxter. “The pharmaceutical industry is not interested in giving less treatment. This study is a great example of how NIH funding can have a major and immediate impact on the lives of cancer patients.”

The data for the study were pooled from these trials: SCOT in the United Kingdom, Denmark, Spain, Australia, Sweden, and New Zealand; TOSCA in Italy; Alliance/SWOG 80702 in the United States and Canada; IDEA France (GERCOR/PRODIGE) in France; ACHIEVE in Japan; and HORG in Greece.

Shi Q, Sobrero AF, Shields AF, et al. Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration. 

According to findings presented at the 2017 ASCO Annual Meeting, patients with low-risk advanced colon cancer would benefit from a reduction in chemotherapy post-surgery, without increasing risk of recurrence, to reduce risk of neuropathy.

Shorter Adjuvant Chemo in Colon Cancer Is Effective, Reduces Neuropathy Risk

Adverse reactions occurring at an overall incidence of <10% of patients receiv- ing palbociclib plus letrozole in Study 1 included alanine aminotransferase in- creased (9.9%), aspartate aminotransferase increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%).

Additional adverse reactions occurring at an overall incidence of less than 10.0% of patients receiving palbociclib plus fulvestrant in Study 2 included as- thenia (7.5%), aspartate aminotransferase increased (7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine amino- transferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile neutropenia (0.9%).

Based on animal studies, IBRANCE can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with IBRANCE.

Colitis and gastrointestinal perforation, including fatal outcomes, have been re- ported in patients taking MEKINIST as a single-agent and when administered with dabrafenib.

Across clinical trials of trametinib administered as a single agent (N = 329) and with dabrafenib (N = 559), colitis occurred in 0.6% of patients and gastrointesti- nal perforation occurred in 0.3% of patients.

​Monitor patients closely for colitis and gastrointestinal perforations.

Patients receiving trametinib are advised tocontact their healthcare provider immediately if they experience diarrhea, stomach or abdominal pain, fever, or nausea

A Pregnancy Safety Surveillance Study has been established to collect informa- tion about pregnancies in women who have received ipilimumab.

Healthcare providers are encouraged to enroll patients or have their patients en- roll directly by calling (844)-593-7869.

Lactation—it is not known whether ipilimumab is present in human milk.

Healthcare providers should review steps for appropriate administration of filgrastim-sndz with prefilled syringe with patients and caregivers, particularly if the entire prefilled dosage will not be used

Patients who self-administer prefilled syringes should receive instructions about the dangers of reusing needles and syringes, the importance of proper disposal, and importance of informing healthcare provider if difficulty occurs when mea- suring or administering partial contents of prefilled syringe.

Recent changes to FDA labels regarding adverse events.

May Adverse Events Report: FDA Labeling Changes

Fatal and serious skin reactions have been reported with bendamustine hydrochloride injection treatment in clinical trials and postmarketing safety reports, including the toxic skin reactions Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms, and rash.

Skin reaction events occurred when bendamustine hydrochloride injection was given as a single agent and in combination with other anticancer agents or allopurinol.

Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients.

Most cases of hepatoxicity were reported within the first 3 months of starting therapy.

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity.

Niolotinib is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome.

Patients should be advised that treatment with nilotinib can cause serious thrombocytopenia, neutropenia, and anemia; possibly life-threatening, abnormal heartbeat; an increased risk of pancreatitits, tumor lysis syndrome; and fluid retention.

Patients should be cautioned about symptoms suggestive of these adverse events and advised to seek immediate medical attention if such symptoms occur.

The potential for serious adverse reactions in nursing infants whose mothers are being treated with nilotinib is unknown. Because many drugs are excreted in human milk, physicians should decide whether to advise nursing mothers to discontinue nursing or stop nilotinib treatment based on the importance of the drug to the mother.

Dinutuximab causes serious neurologic adverse reactions including severe neuropathic pain and peripheral neuropathy.

Severe neuropathic pain occurs in the majority of patients. Administer intravenous opioids prior to, during, and for 2 hours following completion of dinutuximab infusion.

Permanently discontinue dinutuximab in patients with peripheral motor neuropathy of grade 2 or greater severity.

Urinary retention that persists for weeks to months following discontinuation of opioids has occurred in patients treated with dinutuximab; permanently discontinue the drug if retention does not resolve after opioid therapy ends.

Transverse myelitis and reversible posterior leukoencephalopathy syndrome (RPLS) have occurred in patients treated with dinutuximab. Permanently discontinue dinutuximab in patients who develop transverse myelitis and in patients with signs and symptoms of RPLS, such as severe headache, hypertension, visual changes, lethargy, or seizures.

FDA’s Drug Safety Labeling Changes database

The adverse events report featuring FDA labeling changes for bendamustine hydrochloride, nilotinib, dinutuximab.

April Adverse Events Report: FDA Labeling Changes

A multipronged attack on the tumor vasculature network is at the heart of a recently launched clinical trial aimed at developing new therapeutic options for women with advanced, recurrent, platinum-resistant ovarian cancer. The novel agent fosbretabulin tromethamine is being combined with bevacizumab (Avastin) and physician’s choice of either paclitaxel or pegylated liposomal doxorubicin in the experimental arm of the phase II/III FOCUS study (

). The regimen will be compared with bevacizumab plus chemotherapy.

In the single-arm, phase II, GOG-01861 study, the combination demonstrated a median progression-free survival of 7.3 months compared with 4.8 months for bevacizumab alone and a 35.7% overall response rate versus 28.2%, respectively.

Fosbretabulin and bevacizumab both target vascular signaling but in different ways, explained principal investigator Krishnansu S. Tewari, MD, director of research in the Division of Gynecologic Oncology at the University of California, Irvine. He said the triplet regimen is "very promising" for patients who are particularly in need of new therapies, noting that thus far, only 1 randomized phase III clinical trial in the platinum-resistant ovarian cancer space has met its primary endpoint.

In GOG-01861, the combination did not result in any unexpected signals Tewari said; however, grade 3 hypertension was observed more in the combination arm. Investigators in the FOCUS study will be watching carefully for cardiovascular side effects, including hypertension and sinus tachycardia among patients who receive both vascular-targeting drugs.

The FOCUS study will be conducted in 2 stages. In the first part, 80 patients will be randomized to the experimental 3-drug regimen versus the control; up to 4 interim analyses will be conducted so that researchers can determine the safety and efficacy of the novel strategy. The second part of the study will randomize approximately 350 patients to the same treatment arms.

The trial is open to women aged 18 years and older with confirmed platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received ≥1 prior platinum-based regimens and have measurable disease. Participants receiving doxorubicin must have left ventricular ejection fraction ≥45% at baseline assessment.

Mateon Therapeutics, which is sponsoring the FOCUS trial, also is studying the drug in combination with pazopanib in ovarian cancer that is recurrent after platinum-containing therapy.

In a current phase II/III clinical trial for patients with advanced, recurrent, platinum-resistant ovarian cancer, the novel agent fasbretablin tromethamine is combined with bevacizumab (Avastin) and either paclitaxel or pegylated liposomal doxorubicin.

Anita Shaffer