Recent approvals in non–small cell lung cancer (NSCLC) have expanded treatment options both in the neoadjuvant and adjuvant settings, according to Jane Yanagawa, MD. As a result, biomarker testing for patients with earlier-stage disease is beginning to solidify a role in routine practice to guide treatment decision-making.

The need for enhancing treatment choices for patients with resectable NSCLC is evident in statistics showing that 5-year survival rates range from 92% for patients with stage IA1 disease to 36% for those with stage IIIA tumors.2 “This suggests that there’s a lot of room for improvement beyond just operating on these patients,” Yanagawa said during a presentation at the 2022 National Comprehensive Cancer Network (NCCN) Annual Conference in April.

Yanagawa is a thoracic surgeon at UCLA Jonsson Comprehensive Cancer Center and an associate professor at the David Geffen School of Medicine at UCLA, both in Los Angeles, as well as director of thoracic surgery at UCLA Santa Monica Medical Center, all in California. As a surgeon, Yanagawa said she refers patients who may qualify for preoperative or adjuvant therapy for consultation with a medical oncologist. “You always have to balance the benefit with the risks,” she said, including whether earlier use of therapy will negatively affect surgical outcomes.

Findings from clinical trials conducted during the 1990s have established a role for chemotherapy combinations in patients with early-stage NSCLC in preoperative and postoperative settings.

 During the past 18 months, the repertoire for early-stage disease has been expanded with 3 key approvals: osimertinib (Tagrisso) for the adjuvant treatment of patients with 

; atezolizumab (Tecentriq) as adjuvant therapy for patients with PD-L1–positive tumors

; and nivolumab (Opdivo) plus chemotherapy as neoadjuvant therapy.

 The FDA’s decision on the nivolumab regimen in March 2022 marked the agency’s first approval for neoadjuvant therapy for early-stage NSCLC.

NCCN guidelines for resectable early-stage NSCLC now include neoadjuvant and adjuvant regimens with chemotherapy, targeted therapy, and immunotherapy (

). The approvals for osimertinib and atezolizumab will change practice for biomarker testing, Yanagawa said.

Whereas NCCN guidelines recommend broad biomarker testing for patients with advanced or metastatic disease,

patients with stage IB to IIIA disease should receive 

 or PD-L1 testing if they are being considered for osimertinib or atezolizumab therapy, respectively. “PD-L1 and 

 mutations are now really important to determine whether patients need adjuvant therapy after their lung resections,” Yanagawa said. She added that screening for 

 alterations also may be necessary before considering a neoadjuvant nivolumab regimen because patients with those aberrations were excluded from the study population in the pivotal trial.

During her presentation, Yanagawa reviewed findings from 4 key studies involving NCCN guideline-recommended regimens in the neoadjuvant and adjuvant settings:

—Postoperative cisplatin-based chemotherapy significantly improved overall survival (OS) and diseasefree survival (DFS) in patients with resected stage IB to IIIA NSCLC, according to a pooled analysis of clinical trial results by the LACE Collaborative Group.4

After a median follow-up of 5.2 years, results showed an absolute benefit of 5.4% in OS and 5.8% in DFS among the total population of patients with stage IA to III who received adjuvant chemotherapy (n = 2281) compared with those who did not (n = 2303).

The findings translated into statistically significant HRs of 0.89 (95% CI, 0.820.96; 

 = .005) for OS and 0.84 (95% CI, 0.78-0.91; 

 < .001) for DFS. The benefit varied with stage of disease; patients with stage IA fared better without chemotherapy, whereas those with stages II or III disease derived the most benefit.

—Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is approved for adjuvant therapy after tumor resection in patients with NSCLC whose tumors harbor 

 exon 19 deletions or exon 21 L858R mutations.

The FDA’s December 2020 approval in this setting is based on findings from the phase 3 ADAURA trial (NCT02511106) in which 682 patients with stage IB to IIIA NSCLC were randomized postoperatively to receive either osimertinib or placebo with or without platinum-based chemotherapy for up to 3 years.

At 24 months, the DFS rate among participants with stage II to IIIA disease, the primary end point of the study, was 90% (95% CI, 84%-93%) in patients who received osimertinib vs 44% (95% CI, 37%-51%) in the placebo group, which translated into an HR of 0.17 (99.06% CI, 0.11-0.26; 

 < .001). In the overall population, the DFS rate was 89% (95% CI, 85%-92%) with osimertinib and 52% (95% CI, 46%-58%) with placebo, for an HR of 0.20 (99.12% CI, 0.14-0.30; 

—Atezolizumab is indicated for patients with stage II to IIIA NSCLC who have undergone resection followed by platinum-based chemotherapy and have PD-L1 expression of 1% or greater on tumor cells, as detected by the Ventana PD-L1 (SP263) Assay. The FDA approved the indication for the PD-L1 immune checkpoint inhibitor in October 2021 based on data from the phase 3 IMpower010 trial (NCT02486718).

After a median follow-up of 32.2 months, the median DFS in months was not evaluable (NE) for the 248 patients in the population defined in the indication who received atezolizumab therapy (95% CI, 36.1-NE) compared with 35.3 months (95% CI, 29.0-NE) for the 228 participants in this group who had best supportive care (HR, 0.66; 95% CI, 0.50-0.88; 

Among all patients with stage II to IIIA disease who participated in the study (N = 882), atezolizumab therapy also showed a statistically significant advantage (HR, 0.79; 96% CI, 0.64-0.96; 

 = .02), with a clinically enriched benefit in patients whose tumors expressed PD-L1.

—The combination of nivolumab and platinum-doublet chemotherapy was approved based on findings from the phase 3 CHECKMATE 816 trial (NCT02998528). In all, 358 patients with stage IB (≥ 4 cm), II, or IIIA resectable NSCLC and measurable disease were randomized to receive the novel regimen or chemotherapy alone followed by resection.

The primary end points were event-free survival (EFS), defined as the time from randomization to any disease progression, and pathological complete response (pCR), described as 0% residual viable tumor cells in the primary tumor and lymph nodes.

After a minimum follow-up of 21 months, the median EFS was 31.6 months (95% CI, 30.2-not reached) in the nivolumab arm compared with 20.8 months (95% CI, 14.0-26.7) in the chemotherapy group (HR, 0.63; 97.38% CI, 0.43-0.91; 

 = .005). The pCR rate among patients who received nivolumab was 24.0% (95% CI, 18.0%31.0%) vs 2.2% (95% CI, 0.6%-5.6%) for those who received chemotherapy alone (OR, 13.49; 99% CI, 3.49-55.75; P < .001).

Of note, 83.2% of patients treated with the neoadjuvant nivolumab regimen underwent definitive surgery vs 75.4% of those treated with chemotherapy alone, demonstrating that the use of preoperative therapy did not decrease the ability to perform surgery.

Before systemic therapies can be considered, the underlying question of whether the patient is a candidate for surgery must be answered. After diagnosis and staging, physiologic parameters are assessed, Yanagawa said.

These include pulmonary function testing, with surgeons seeking to predict before surgery what the postresection levels of forced expiratory volume in 1 second (FEV1 ) and diffusion capacity of the lung for carbon monoxide (DLCO) would be. The assessment is based on the patient’s anatomy and how many segments in each lobe would be left after the operation, Yanagawa said. “If you calculate a predicted postoperative FEV1 or DLCO, and you believe that after your planned operation that person will be left with FEV1 or DLCO of less than 40%, there will be an increased risk for morbidity and mortality after the operation,” she said.

Because these predictions are based on normal lung function, Yanagawa said, a more accurate assessment may be obtained with the addition of a V/Q scan, which evaluates differential perfusion and ventilation to different portions of the lung. Additionally, patients undergoing a pneumonectomy may need a 2-dimensional transthoracic echocardiogram to determine pulmonary arterial pressures. Patients with underlying coronary risk factors may need a preoperative cardiac stress test.

“[Individuals] usually think of lung resections as just affecting the lungs,” Yanagawa said. “But in addition to the lung parenchyma, you’re also affecting the pulmonary arterial system.… If you’re removing an entire side of the lung, you are suddenly shunting all the blood through the heart to only 1 side, and so that can have a major impact on pulmonary arterial pressures.

“Patients with baseline pulmonary hypertension may not be candidates for certain lung resections,” she added. “Although this operation doesn’t directly impact the heart, a common complication after lobectomy is atrial fibrillation, and there can be inflammation around the heart. For patients who have risk factors for coronary artery disease, a cardiac stress test is sometimes an important part of the preoperative workup.”

Beyond these variables, there are many other “more subtle factors” that must be considered before proceeding to surgery, some of which may surprise oncologists who do not perform surgery, Yanagawa said. She noted findings from a recent survey of experts conducted by the American Association for Thoracic Surgery.

The experts ranked use of home oxygen/underlying severe lung disease, frailty, and predicted postoperative DLCO as the top 3 of 16 risk factors to consider for patients with stage I NSCLC being evaluated for lobectomy (

). Notably, the experts ranked age as a sole factor as No. 14 on the list of risk factors, Yanagawa said. In patients 75 years or older, the extent of surgical resection rather than age alone has been associated with higher 30-day mortality and comorbidities helped increase postoperative complications. Meanwhile, surgical resection has resulted in low mortality rates and satisfactory outcomes in patients 82 years or older with stage I lung cancer.

“Even not that long ago, a lot of patients who are older were not being referred to local therapies for their early-stage lung cancer purely because of their age,” Yanagawa said. “But that has changed a lot in the past decade with improvements of local therapies and increasingly elderly patients are getting treated with either SBRT [stereotactic body radiation therapy] or minimally invasive surgery for their stage I non–small cell lung cancer.”

Yanagawa J. Non-small cell lung cancer: management of patients with resectable disease. Presented at: 2022 National Comprehensive Cancer Network Annual Conference; April 1, 2022; virtual. https://bit.ly/3rWRqpM

Goldstraw P, Chansky K, Crowley J, et al; on behalf of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Boards, and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer. 

 2016;11(1):39-51. doi:10.1016/j.jtho.2015.09.009

Rosell R, Felip E, Maestre J, et al. The role of chemotherapy in early non-small-cell lung cancer management. 

 2001;34(suppl 3):S63-S74. doi:10.1016/s0169-5002(01)00376-2

Pignon JP, Tribodet H, Scagliotti GV, et al; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. 

 2008;26(21):3552-3559. doi:10.1200/JCO.2007.13.9030

FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed April 28, 2022. https://bit.ly/3MFbyEq

FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. FDA. October 15, 2021. Accessed April 28, 2022. https://bit.ly/3MyTsnG

FDA approves neoadjuvant nivolumab and platinum-doublet chemotherapy for early-stage non-small cell lung cancer. FDA. March 4, 2022. Accessed April 28, 2022. https://bit.ly/3vpPUhN

NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2022. Accessed April 29, 2022. https://bit.ly/3kv2eai

Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected 

 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071

Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). 

 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500

Forde PM, Spicer J, Lu S, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. 

 Published online April 11, 2022. doi:10.1056/NEJMoa2202170

Forde PM, Spicer J, Lu S, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial. 

 2021;81(suppl 13):CT003. doi:10.1158/1538-7445.AM2021-CT003

Pennathur A, Brunelli A, Criner GJ, et al; AATS Clinical Practice Standards Committee: Thoracic Surgery. Definition and assessment of high risk in patients considered for lobectomy for stage I non–small cell lung cancer: the American Association for Thoracic Surgery expert panel consensus document. 

 2021;162(6):1605-1618.e6. doi:10.1016/j.jtcvs.2021.07.030

This article was originally published on 

® as “NCCN Guidelines Affirm New Options for Resectable NSCLC.”

Articles

Updates to the NCCN guidelines for patients with resectable early-stage NSCLC now include neoadjuvant and adjuvant regimens with chemotherapy, immunotherapy, and targeted therapies, which promise to change biomarker testing practice.

NCCN Guidelines Reflect Recent Advances in Resectable NSCLC

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

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).

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.

Anita Shaffer

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