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FDA Actions & Updates

The latest approvals, designations, and new indications from the U.S. Food and Drug Administration for oncology drugs.

Wednesday, May 15, 2019

The FDA has approved avelumab in combination with axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC). This is the first FDA approval for an anti-PD-L1 therapy as part of a combination regimen for patients with advanced RCC.

The approval of avelumab in combination with axitinib was based on positive results from the phase III JAVELIN Renal 101 study (NCT02684006), in which the combination significantly improved median progression-free survival (PFS) compared with sunitinib by more than 5 months in the intent-to-treat (ITT) patient population (HR: 0.69 [95% CI: 0.56–0.84]; 2-sided p-value=0.0002; median PFS for avelumab in combination with axitinib: 13.8 months [95% CI: 11.1-NE]; sunitinib: 8.4 months [95% CI: 6.9-11.1]). The ITT population included patients regardless of PD-L1 expression and across IMDC (International Metastatic Renal Cell Carcinoma Database) prognostic risk groups (favorable 21%, intermediate 62% and poor 16%).

"As we look to continue to improve outcomes for people with advanced RCC, new treatment approaches have the potential to benefit patients," said Robert J. Motzer, MD, Jack and Dorothy Byrne Chair in Clinical Oncology, Memorial Sloan Kettering Cancer Center, and principal investigator for JAVELIN Renal 101. "With [this] FDA approval of avelumab in combination with axitinib, we can now offer patients with advanced RCC a first-line treatment option that combines a PD-L1 immunotherapy with a well-known VEGFR TKI to provide a significant reduction in the risk of disease progression or death and doubling of the response rate compared with sunitinib."

"A kidney cancer diagnosis is life-changing for both patients and their loved ones, and having a treatment strategy for their disease quickly becomes a priority," said Dena Battle, President, KCCure. "The approval of new treatments such as avelumab in combination with axitinib gives patients with advanced RCC much-needed options."

There is a significant unmet need for first-line treatments that delay progression and have an acceptable safety profile. Approximately 20 percent to 30 percent of patients are first diagnosed with RCC at the advanced stage, and 30 percent of patients treated for an earlier stage go on to develop metastases. About half of patients living with advanced RCC do not go on to receive additional treatment after first-line therapy.

In JAVELIN Renal 101, the objective response rate (ORR) was doubled in the ITT population with avelumab in combination with axitinib versus sunitinib (51.4% [95% CI: 46.6-56.1] vs. 25.7% [95% CI: 21.7-30.0]). With a median overall survival (OS) follow-up of 19 months, data for the trial's other primary endpoint of OS were immature, with 27 percent of deaths in the ITT population, and the trial is continuing as planned. The most common adverse reactions (≥20%) were diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache. Serious adverse reactions occurred in 35 percent of patients receiving avelumab in combination with axitinib. The incidence of major adverse cardiovascular events (MACE) was higher with avelumab in combination with axitinib versus sunitinib. Findings from the study have been published in The New England Journal of Medicine (2019;380:1103-1115).

The European Medicines Agency validated the Type II variation application for avelumab in combination with axitinib in advanced RCC in March 2019, and a supplemental application for avelumab in combination with axitinib in unresectable or metastatic RCC was submitted in Japan in January 2019.

Monday, May 13, 2019

The FDA has granted Orphan Drug Designation for AL101, a potent and selective inhibitor of gamma secretase-mediated Notch signalling, for the treatment of adenoid cystic carcinoma (ACC).

Orphan Drug Designation is granted to drug therapies intended to treat diseases or conditions that affect fewer than 200,000 people in the U.S. 

ACC is a rare form of cancer. In the U.S., there are approximately 566,000 people diagnosed with cancer each year, and only about 1,224 of them are diagnosed with ACC. According to the Adenoid Cystic Carcinoma Organization International, there are approximately 14,873 Americans alive today living with this disease. Current treatment options include surgery, chemotherapy and/or radiation therapy; however, there is no approved drug for the treatment of ACC. 

AL101 is a gamma secretase inhibitor developed as a Notch inhibitor for oncology indications. Notch signaling pathway plays an important role in tumorigenesis in several solid and hematological malignancies. Upon ligand binding of the Notch receptor, an important step in the activation of Notch receptors is cleavage by gamma secretase, which frees the Notch intracellular signaling domain.

AL101 is currently in phase II for adenoid cystic carcinoma patients with tumor bearing Notch activating mutations (ACCURACY). 

Friday, May 3, 2019

Amy Abernethy, MD, PhD, Principal Deputy Commissioner, and Jeff Shuren, MD, JD, Director of the Center for Devices and Radiological Health released the following statement on the FDA's new efforts to protect women's health and help to ensure the safety of breast implants:

There has been a growing discussion in recent months around the safety of certain breast implants, with regulatory agencies around the world weighing the risk of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). It's an issue that has been a priority for us at the FDA since 2011 when we warned women that the available information at the time indicated that there is a risk for women with breast implants, especially those with textured implants, for developing this disease.

Since that time, we have worked diligently to fill the gaps in knowledge, such as evaluating the body of available evidence regarding the safety and risks of breast implants, including concerns specific to textured implants and the risk of BIA-ALCL. The agency has undertaken several steps to better understand this issue, including an in-depth review of post-approval study data, medical device reports, scientific literature and breast implant-specific registries, and public discussions. But this is not the only issue we've been considering with respect to breast implants.

The agency has regularly communicated about additional risks associated with breast implants, such as capsular contracture and implant rupture. And we have heard from patients concerned that their implants may be connected to health conditions involving their immune system's response to these devices, resulting in a variety of symptoms like chronic fatigue, cognitive issues, joint and muscle pain. While the FDA doesn't have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some women experience systemic symptoms that may resolve when their breast implants are removed, referred to by some patients and health care professionals as breast implant illness. We believe women considering a breast implant should be aware of these risks. As we describe below, we are taking steps to better characterize the condition and its risk factors, and are considering ways to help to ensure women have all of the information they need to make informed decisions about whether to obtain breast implants or to remove existing breast implants in an effort to reverse systemic symptoms.

Most recently, we discussed these important issues in a public advisory committee meeting in March. In the pursuit of our mission to protect the public health, one of the most important things we do as regulators is to listen to the experiences and perspectives of patients, medical and scientific experts and other stakeholders related to medical products. The meeting covered a range of important topics on breast implant safety, including the use of surgical mesh in breast implant surgery, characterization of BIA-ALCL incidence and risk factors, and methods for assessing systemic symptoms. During the 2-day meeting, we listened carefully to the insightful comments and personal stories from a broad range of public, scientific, medical and other stakeholders. These insights have been invaluable in growing our understanding of the potential risks associated with breast implants and the need for further efforts to help to ensure appropriate patient protections and improve breast implant safety.

To that end, the information we've garnered, from this meeting and other ongoing efforts, makes clear there is an opportunity to do more to protect women considering breast implants. And [now], we are announcing several new steps we have taken and are considering aimed at helping to ensure that women have access to the information they need about breast implants to make informed decisions and to further drive evidence generation that will help the FDA make the most appropriate scientific regulatory decisions moving forward.

First, we will take steps to improve the information available to women and health care professionals about the risks of breast implants that would include addressing the risk of BIA-ALCL, the greater risk of BIA-ALCL with textured implants, and the risk of developing systemic symptoms that would contribute to the patient-provider discussion about breast implants. We are also looking at ways to incorporate product ingredient information into the labeling in a way that is easy for patients to understand. The FDA would work with stakeholders, including patient groups, on the content and format of any labeling changes proposed or recommended by the FDA, which could include a boxed warning and a patient decision checklist, and would work with manufacturers on implementing any changes to the information they provide to health care professionals and patients, including labeling.

We are considering these actions to help to ensure that all women who consider breast implants have the information they need to have thoughtful and balanced discussions with their health care professional about both the benefits and risks of breast implants based on clear information reflecting the most current understanding of these issues.

As we undertake this effort, we recognize that there is a need to help to ensure that information reaches health care professionals and women. We are aware that there are some health care professionals, such as gynecologists, dermatologists, internists and pathologists, who may not be fully aware of these breast implant risks, like BIA-ALCL and systemic symptoms. We are committed to doing what we can to reach them with this important information, including continuing the outreach we started with our Letter to Health Care Providers to educate the medical community about BIA-ALCL and other risks of breast implants.

We also plan to work with the pathology community to educate pathologists about testing for this lymphoma specific to breast implants. In addition, we're committed to continuing to update the public about any new information related to breast implant risks, as well as updating and improving the communication tools we have for women on our website.

We will continue our regular updates about the known global medical device reports for BIA-ALCL, as we have done since 2011. Moving forward, we plan to also regularly communicate information we receive through medical device reports about systemic symptoms experienced by patients with breast implants. We provided information at the two-day advisory committee meeting on medical device reports we've received that mention systemic symptoms described by some as breast implant illness, and we plan to continue sharing the numbers of medical device reports on these symptoms.

We are also announcing a change in how breast implant manufacturers file medical device reports with the FDA. We appreciate the value to the public in ensuring this information from medical device reports is readily available to them. In an effort to promote greater public transparency, the FDA has ended all summary reporting of breast implant medical device reports and has notified breast implant manufacturers of this decision. This is part of a larger effort to end the alternative summary reporting program for all medical devices, which we intend to complete in the coming weeks. This program was established in 1997 to more efficiently review adverse events for well-established risks but was not allowed for patient deaths and unusual, unique or uncommon adverse events, which, in the case of breast implants, included BIA-ALCL. Alternative summary reports were not previously available in our public database for medical device reports, Manufacturer and User Facility Device Experience (MAUDE).

Moving forward, breast implant manufacturers will be required to file individual medical device reports that will be publicly available in MAUDE. For past data received through summary reporting, the agency will also be making this data, including alternative summary reports for all devices under the program, publicly available in the coming weeks.

We believe these steps for more transparent medical device reports will contribute to greater public awareness of breast implant adverse events. Increased public awareness of the number of adverse events may contribute to a woman's own understanding of the risks of breast implants, but, as with any medical device report, it's important to note that generally the number of reports received cannot be used to determine the frequency with which a particular adverse event occurs. The information in medical device reports is important, but they are only one tool that contributes to our understanding of breast implants. Further, it is important that people understand that the reports are just that – a report by an outside party. The agency has not verified that they are accurate, nor that the issue was in fact caused by the device. For this reason, among others, these reports cannot be used alone to determine an incidence rate, causation or associations as many reports can be duplicative or incomplete.

Partnering with registries, such as the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILEExternal Link Disclaimer), which collects real world data on patients with BIA-ALCL diagnoses, and the new National Breast Implant Registry (NBIRExternal Link Disclaimer), which collects real world data on the safety and performance of breast implants, is one way in which we seek to gain greater insight and more comprehensive information about women's experiences with breast implants.

We expect that both breast implant registries will greatly contribute to helping us evaluate data from providers regarding their patients with breast implants. The data already made available to us from the PROFILE registry provides additional information about patients diagnosed with BIA-ALCL. However, more needs to be done to increase the number of health care professionals contributing to the registries and types of information collected by the registries.

We believe this work with the registries, along with our efforts to address concerns in how the post-approval studies are conducted, will help improve the evidence generated on breast implants and can greatly contribute to our understanding and further assessment of BIA-ALCL, systemic symptoms and other potential long-term risks from breast implants. Better evidence generation leads to more robust and scientifically-sound regulatory decisions.

A few of our international counterparts have started to initiate actions to ban or restrict sales of some textured breast implants, based on concerns about BIA-ALCL. In those markets, there are textured implants that are not marketed in the U.S. and where the use of textured implants is much higher, sometimes as high as 80 percent market share. In 2018, textured breast implants represented less than 10 percent of breast implants sold in the U.S. The type of macro-textured implants targeted by some of our international counterparts represents less than 5 percent of breast implants sold here. At this time, the FDA does not believe that, on the basis of all available data and information, the device meets the banning standard set forth in the Federal Food, Drug and Cosmetic Act.

The FDA believes regulatory action must be based on scientific data. While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants and many reports do not include the surface texture of the implant at the time of diagnosis. We are focused on strengthening the evidence generated to help inform future regulatory actions and to assure that women and providers are adequately informed of the risk of BIA-ALCL, including that the risk is higher with the use of textured implants, albeit still low. We are still investigating the cause of the association and we will continue to monitor, assess and report our findings as we continue to strengthen our evidence collected so that women and providers can be better informed about BIA-ALCL as they consider breast implants.

Taken together, we believe these efforts to improve communication and focus on evidence generation will contribute significantly to improving the safety of breast implants and want to share that many of these efforts are already underway. We are committed to making a difference for women's health and will continue working towards ensuring we understand the benefits and risks of these devices, and that women have the most complete information available to make important breast implant decisions.

Thursday, May 2, 2019

The FDA has approved a supplemental New Drug Application (sNDA) to update the U.S. Prescribing Information for ivosidenib, an IDH1 inhibitor, to include adult patients with newly diagnosed acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy.

The sNDA was granted Priority Review and accepted under the FDA's Real-Time Oncology Review pilot program, which aims to make the review of oncology drugs more efficient by allowing the FDA access to clinical trial data before the information is formally submitted to the agency. Ivosidenib received initial FDA approval in July 2018 for adult patients with relapsed or refractory (R/R) AML and an IDH1 mutation.

AML is the most common acute leukemia affecting adults with approximately 20,000 new cases estimated in the U.S. each year. AML patients are typically older or have comorbidities that preclude the use of intensive chemotherapy. These patients typically have a worse prognosis and poor outcomes. The majority of patients with AML eventually relapse. The 5-year survival rate is approximately 28 percent. For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia. IDH1 mutations have been associated with negative prognosis in AML.

"The phase I results for ivosidenib demonstrated that this oral, single agent therapy can induce durable responses in newly diagnosed AML patients with an IDH1 mutation," said Gail J. Roboz, MD, Professor of Medicine, Director of the Leukemia Program and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. "Many patients included in the study had features associated with particularly aggressive and challenging forms of AML, including secondary disease, adverse risk genetics and prior treatment with hypomethylating agents."

The efficacy of ivosidenib was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly diagnosed AML with an IDH1 mutation who were assigned to receive a 500 mg daily dose. The cohort included patients who were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy (baseline ECOG performance status of ≥2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, or creatinine clearance <45 mL/min). Patients had a median age of 77 years (range of 64 to 87) and 68 percent had AML with myelodysplasia-related changes. The primary endpoint is the combined complete remission (CR) and complete remission with partial hematologic improvement (CRh) rate. CRh is defined as <5 percent of blasts in the bone marrow, no evidence of disease and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

In this trial, ivosidenib demonstrated:

  • CR+CRh rate of 42.9 percent (12 of 28 patients) (95% CI: 24.5, 62.8).
  • The CR rate was 28.6 percent (8 of 28 patients) (95% CI 13.2, 48.7) and the CRh rate was 14.3 percent (4 of 28 patients) (95% CI 4.0, 32.7).
  • Median durations of CR and CR+CRh were not estimable, with 5 patients (41.7%) who achieved CR or CRh remaining on ivosidenib treatment (treatment duration range: 20.3 to 40.9 months) as of the data cutoff.
  • 58.3 percent (7 of 12) of patients who achieved CR or CRh were in remission at 1 year after receiving treatment.
  • For patients who achieved a CR or CRh, the median time to best response of CR or CRh was 2.8 months (range, 1.9 to 12.9 months).
  • Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 7 (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period.
  • Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 6 (54.5%) remained transfusion independent during any 56-day post-baseline period.
The safety profile of single-agent ivosidenib was evaluated in 28 patients with newly diagnosed AML with an IDH1 mutation treated with a dose of 500 mg daily. The median duration of exposure to ivosidenib was 4.3 months (range, 0.3 to 40.9 months). In the clinical trial, 25 percent (7 of 28) of patients treated with ivosidenib experienced differentiation syndrome, which can be fatal if not treated. 

Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. QTc interval prolongation occurred in patients treated with ivosidenib. The most common adverse reactions (≥20%) of any grade in patients with newly diagnosed AML were diarrhea, fatigue, decreased appetite, edema, nausea, leukocytosis, arthralgia, abdominal pain, dyspnea, myalgia, constipation, differentiation syndrome, dizziness, electrocardiogram QT prolonged, mucositis, and vomiting.

Monday, April 29, 2019

The FDA has approved pembrolizumab in combination with axitinib, a tyrosine kinase inhibitor, for the first-line treatment of patients with advanced renal cell carcinoma (RCC). The approval is based on findings from the pivotal phase III KEYNOTE-426 trial, which demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) for pembrolizumab in combination with axitinib compared to sunitinib. 

Consistent results were observed across pre-specified subgroups, IMDC risk categories, and PD-L1 tumor expression status. For the main efficacy outcome measures of OS and PFS, the pembrolizumab-axitinib combination reduced the risk of death by 47 percent compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). For PFS, the pembrolizumab-axitinib combination showed a reduction in the risk of progression of disease or death of 31 percent compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). The ORR, an additional efficacy outcome measure, was 59 percent for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36 percent for those who received sunitinib (95% CI, 31-40) (p<0.0001). This is the first indication for pembrolizumab in advanced RCC, the most common type of kidney cancer, and the first anti-PD-1 therapy FDA-approved as part of a combination regimen that significantly improved OS, PFS, and ORR versus sunitinib in patients with advanced RCC.

Immune-mediated adverse reactions, which may be severe or fatal, can occur with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, severe skin reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation (HSCT). Based on the severity of the adverse reaction, pembrolizumab should be withheld or discontinued and corticosteroids administered if appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab can cause fetal harm when administered to a pregnant woman.

"Given the aggressive nature of the disease, many patients with advanced renal cell carcinoma need additional treatment options that can help improve survival outcomes," said Brian Rini, MD, a medical oncologist at Cleveland Clinic Cancer Center and Professor of Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. "Pembrolizumab in combination with axitinib offers an important new therapeutic option for physicians to consider when approaching initial treatment for patients newly diagnosed with advanced renal cell carcinoma." 

Study Details

The approval was based on data from the pre-specified interim analysis of the phase III KEYNOTE-426 trial, a randomized, multi-center, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable vs. intermediate vs. poor) and geographic region (North America vs. Western Europe vs. "Rest of the World"). Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible.

Patients were randomized (1:1) to one of the following treatment arms:

  • pembrolizumab 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily (n=432).
  • Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks (n=429).

Among the 861 patients, the study population characteristics were: median age of 62 years (range, 26 to 90); 38 percent age 65 or older; 73 percent male; 79 percent white and 16 percent Asian; 19 percent and 80 percent of patients had a baseline Karnofsky Performance Status of 70-80 and 90-100, respectively; and patient distribution by IMDC risk categories was 31 percent favorable, 56 percent intermediate, and 13 percent poor.

Treatment with the pembrolizumab-axitinib combination continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease or unacceptable toxicity. The main efficacy outcome measures were OS and PFS as assessed by BICR according to modified RECIST v1.1. Additional efficacy outcome measures included ORR, as assessed by BICR.

The trial demonstrated statistically significant improvements in OS, PFS, and ORR in patients randomized to receive the pembrolizumab-axitinib combination compared to sunitinib.

With a median follow-up time of 12.8 months (range, 0.1 to 22 months), OS was significantly improved in patients who received the pembrolizumab-axitinib combination compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). Estimated 12-month OS rates were 90% (95% CI, 86-92) with the pembrolizumab-axitinib combination versus 78% (95% CI, 74-82) with sunitinib. Median OS was not reached with either treatment regimen. PFS was also significantly improved with the pembrolizumab-axitinib combination compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). Median PFS was 15.1 months (95% CI, 12.6-17.7) in patients receiving the pembrolizumab-axitinib combination versus 11.1 months (95% CI, 8.7-12.5) with sunitinib. In the study, the ORR was 59 percent for patients who received the pembrolizumab-axitinib combination (95% CI, 54-64) and 36 percent for those who received sunitinib (95% CI, 31-40) (p<0.0001), with a complete response rate of 6 percent and 2 percent and a partial response rate of 53 percent and 34 percent, for patients receiving the pembrolizumab-axitinib combination versus sunitinib, respectively.

Safety & Adverse Events

In KEYNOTE-426, the safety of pembrolizumab in combination with axitinib was investigated in patients with previously untreated, advanced RCC. The median duration of exposure to the combination therapy of pembrolizumab and axitinib was 10.4 months (range, 1 day to 21.2 months). Fatal adverse reactions occurred in 3.3 percent of patients receiving pembrolizumab in combination with axitinib. Serious adverse reactions occurred in 40 percent of patients receiving pembrolizumab in combination with axitinib. 

Serious adverse reactions in ≥1 percent of patients receiving pembrolizumab in combination with axitinib included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction of either pembrolizumab or axitinib occurred in 31 percent of patients; 13 percent pembrolizumab only, 13 percent axitinib only, and 8 percent both drugs. The most common adverse reaction (>1%) resulting in permanent discontinuation of pembrolizumab, axitinib, or the combination was hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). 

The most common adverse reactions (≥20%) in patients receiving in patients receiving pembrolizumab and axitinib were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).