Choosing frontline therapy for patients with metastatic non—small cell 

 (NSCLC) who do not harbor an actionable driver oncogene depends upon PD-L1 expression level and histology, according to Gregory J. Riely, MD, PhD.

The rapid pace, he added, of clinical trial findings during the past 7 months have prompted the evolution in first-line options. “It’s transformed how we treat patients with initial therapy,” said Riely, a medical oncologist who is vice chair of Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center.

To update clinicians on the new landscape in NSCLC, Reily conducted a presentation at the 2018 New York Lung Cancers Symposium, where he explained that patients with PD-L1 expression ≥50% would be candidates for single-agent immunotherapy with pembrolizumab (Keytruda) while those whose status is below that level would be considered for combination PD-1/PD-L1—targeting immunotherapy and chemotherapy. The choice of the combination would then depend upon histology.

Before delving into the details of treatment options, Riely emphasized that the matter of establishing whether a patient has a driver oncogene also is becoming more multifaceted. He said the standard of care requires testing for mutations in 

genes. However, Riely noted that therapies targeting 

 alterations also are in development, demonstrating the value of conducting more extensive testing.

In all, 4 immune checkpoint inhibitors are FDA approved for treating patients with NSCLC: the PD-1 inhibitors pembrolizumab and nivolumab (Opdivo) and the PD-L1 inhibitors atezolizumab (Tecentriq) and durvaulamb (Imfinzi). Pembrolizumab is approved in frontline settings as monotherapy for patients with metastatic NSCLC with PD-L1 expression ≥50% and in combination with chemotherapy regimens. Nivolumab and atezolizumab are indicated for patients who have progressed during or following platinum-containing chemotherapy, while durvalumab is approved for unresectable stage III disease that has not progressed after chemoradiotherapy.

The efficacy of single-agent pembrolizumab for patients with PD-L1 expression ≥50% was first established in findings from the 

In all, 305 patients with previously untreated NSCLC were randomized 1:1 to receive pembrolizumab at 200 mg IV every 3 weeks versus platinum doublet chemotherapy. The estimated 6-month overall survival (OS) rate was 80.2% with pembrolizumab versus 72.4% with chemotherapy (HR for death, 0.60; 95% CI, 0.41-0.89;

Moreover, participants treated with pembrolizumab experienced fewer treatment-related adverse events (AEs) of any grade than did those who received chemotherapy (73.4% vs 90.0%, respectively) and fewer AEs grade ≥3 (26.6% vs 53.3%).1 However, Riely noted that pembrolizumab is associated with immune-related AEs and that patients should be monitored for these effects, particularly those affecting thyroid function.

The findings made “it clear that this was the new standard of care for patients with ≥50% PD-L1” expression, so the next question became whether this would be the case for those whose status was below that threshold.

 study, pembrolizumab monotherapy was tested against the chemotherapy doublet of carboplatin plus paclitaxel or pemetrexed (Alimta) in 1274 patients with previously untreated locally advanced or metastatic NSCLC of any histology with a tumor proportion score (TPS) ≥1%. TPS is defined as the percentage of tumor cells with membranous PD-L1 staining.

The findings confirm the benefit of pembrolizumab therapy for patients with TPS ≥50%, according to results presented at the 2018 ASCO Annual Meeting.

The median OS for this group was 20 months (95% CI, 15.5-24.9) with pembrolizumab compared with 12.2 months (95% CI, 10.4-14.2) with the combination of carboplatin and either paclitaxel or pemetrexed (HR, 0.69; 95% CI, 0.56-0.85; 

The benefit was less pronounced for participants with lower TPS scores. For TPS ≥20%, the median OS with pembrolizumab was 17.7 months (95% CI, 15.3-22.1) versus 13.0 months (11.6-15.3) with chemotherapy (HR, 0.77; 95% CI, 0.64-0.92; 

= .0020). For TPS ≥1%, the median OS was 16.7 months (95% CI, 13.9-19.7) with pembrolizumab versus 12.2 months (95% CI, 11.3-13.3) with chemotherapy (HR, 0.81; 95% CI, 0.71-0.93; 

= .0018). For all patients with TPS ≥1% to 49%, the median OS with pembrolizumab was 13.4 months (95% CI, 10.7-18.2) compared with 12.1 months (95% CI, 11.0-14.0) with chemotherapy (HR, 0.92; 95% CI, 0.77-1.11).

“There’s no clear benefit for pembrolizumab over chemotherapy in this context,” Riely said, of the 1% to 49% group. “The hazard ratio is nearly 1 and the confidence intervals overlap. This tells us that it’s probably not reasonable to move the bar down from 50% to 1% but we can think about that when we see our patients.”

When choosing combination immunotherapy and chemotherapy, the decision about which option hinges on histology, Riely said.

For patients with nonsquamous disease, there are 2 regimens with recently reported results: (1) pembrolizumab plus carboplatin and pemetrexed, and (2) atezolizumab with bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP).

 trial, the pembrolizumab combination demonstrated an improvement in OS compared with chemotherapy alone regardless of PD-L1 expression status. The 12-month OS rate was 69.2% (95% CI, 64.1-73.8) with the pembrolizumab regimen compared with 49.4% (95% CI, 42.1-56.2) for those who received chemotherapy (HR for death, 0.49; 95% CI, 0.38-0.64; 

<.001). Among participants with a TPS <1%, the 12-month OS rate was 61.7% with the pembrolizumab regimen versus 52.5% with chemotherapy alone, which translated into an HR for death of 0.59 (95% CI, 0.38-092).

In the phase III IMpower150 trial, the addition ABCP regimen resulted in improvements in progression-free survival (PFS) and OS compared with bevacizumab, carboplatin, and paclitaxel (BCP). At 12 months, the PFS rate with ABCP was 36.5% (95% CI, 31.2-41.9) versus 18.0% (95% CI, 13.4-22.6) with BCP (stratified HR, 0.62; 95% CI, 0.52-0.74; 

 <.001). At 24 months, the OS rate with ABCP was 43.4% (95% CI, 36.9-49.9) versus 33.7% (95% CI, 27.4-40.0) with BCP, for a stratified HR of 0.78 (95% CI, 0.64-0.96; 

For patients with squamous histology, Riely pointed to findings from the 

 study, which tested carboplatin/paclitaxel or nab-paclitaxel (Abraxane) with and without pembrolizumab.

After a median follow-up of 7.8 months, the median OS for the pembrolizumab-containing regimen was 15.9 months (95% CI, 13.2-not reached) versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; 

 = .001). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.

Additionally, the phase III Impower131 study showed an improvement in PFS with the addition of atezolizumab to frontline carboplatin and nab-paclitaxel. At a median follow-up of 17.1 months, the median PFS was 6.3 months (95% CI, 5.7-7.1) with the addition of atezolizumab versus 5.6 months (95% CI, 5.6-5.7) with chemotherapy alone (HR, 0.71; 95% CI, 0.60-0.85; 

 = .0001). The 12-month PFS rates were 24.7% versus 12.0%, respectively.

However, the immunotherapy regimen has not yet translated into an OS improvement. At the first interim OS analysis, the median OS was 14.0 months (95% CI, 12.0-17.0) with the atezolizumab triplet compared with 13.9 months (95% CI, 12.3-16.4) with chemotherapy alone (HR, 0.96; 95% CI, 0.78-1.18; 

 = .6931). The 12- and 24-month OS rates were 55.6% versus 56.9% and 31.9% versus 24.1%, respectively.

Riely noted that the trial findings are from an early analysis and that OS data might change with further follow-up.

Reck M, Rodriguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1—positive non–small-cell lung cancer. 

Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥1%: open-label, phase 3 KEYNOTE-042 study. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago, IL. Abstract LBA4. abstracts.asco.org/214/AbstView_214_226263.html.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. 

2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.

Socinski MA, Jotte R, Cappuzzo F, et al; Impower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.

 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.

Paz-Ares L, Luft A, Vicente D, et al; KEYNOTE-4017 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer [published online September 25, 2018]. 

Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC. 

 2018;36 (suppl; abstr LBA9000). meetinglibrary.asco.org/record/165951/abstract.

Biomarkers and Histology Play Key Roles in Frontline Metastatic NSCLC Options

Articles

Choosing frontline therapy for patients with metastatic non–small cell lung cancer (NSCLC) who do not harbor an actionable driver oncogene depends upon PD-L1 expression level and histology, according to Gregory J. Riely, MD, PhD.

Frontline Treatment of Metastatic NSCLC Depends on Biomarkers and Histology

Regorafenib (Stivarga) maintained a prolonged overall survival (OS) benefit as second-line therapy for patients with advanced hepatocellular carcinoma (HCC) in a 2-year updated analysis of key findings from the pivotal RESORCE trial, according to results presented at the 2018 International Liver Cancer Association (ILCA) Annual Conference.

In the follow-up data, the multikinase inhibitor improved median OS to 10.7 months (95% CI, 9.1-12.2) compared with 7.9 months (95% CI, 6.4-9.0) with placebo, which translated into a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.51-0.75; 

Those results were highly similar to findings from the primary analysis that prompted the FDA to approve regorafenib in April 2017 for patients with HCC who have been previously treated with sorafenib (Nexavar).

The updated findings are worth revisiting considering regorafenib’s place in the timeline of HCC advancements, according to lead study investigator Jordi Bruix, MD, PhD, who presented the data at ILCA. “This was the trial that suddenly opened an era of more success after 10 years of failures,” said Bruix, director of the Barcelona Clinic Liver Cancer (BCLC) Group at the Hospital Clinic of Barcelona in Spain.

The RESORCE trial (NCT01774344) randomized patients 2:1 to receive regorafenib at 160 mg daily (3 weeks on/1 week off) versus placebo until progression, death, or unacceptable toxicity. In all, 573 patients participated in the study; 379 received regorafenib and 194 were given placebo.

The study recruited patients with radiologic progression during sorafenib treatment who had Child-Pugh A status and BCLC stage B or C disease not amenable to resection or locoregional therapy. The median age was 64 years (range, 54-71) in the regorafenib arm and 62 years (range, 55-68) in the placebo group.

The efficacy population was balanced at baseline between regorafenib and placebo, respectively, for macrovascular invasion (29% vs 28%), extrahepatic disease (70% vs 76%), alpha-fetoprotein ≥400 ng/mL (43% vs 45%), and the presence of cirrhosis (75% vs 74%).

Tolerance to prior sorafenib also was required; this was defined as having taken ≥400 mg daily for at least 20 days of the last 28 days of treatment. Additionally, patients had to be randomized within 10 weeks after their last sorafenib dose.

“We had a very tight definition of tolerance to sorafenib,” Bruix said. “We had a maximum time period between the last period of sorafenib before entrance into the trial. This was intended to secure patients who were upon progression and not indolent cases.”

Bruix noted that regorafenib improved outcomes for the primary OS endpoint as well as the secondary endpoints of progression-free survival, time to progression, disease control rate, and overall response rate. The most common clinically relevant grade 3/4 treatment-related adverse events were hypertension, hand—foot skin reaction, fatigue, and diarrhea.

In the primary analysis, which had a data cutoff of February 29, 2016, the median OS with regorafenib was 10.6 months (95% CI, 9.1-12.1) versus 7.8 months (95% CI, 6.3-8.8) with placebo (HR, 0.62; 95% CI, 0,50-0.78; 

As of January 14, 2018, the data cutoff for the updated analysis, the estimated OS rates for regorafenib compared with placebo at 12, 18, and 30 months were 47% versus 28%, 32% versus 15%, and 16% versus 8%, respectively, Bruix and colleagues reported in their conference abstract. Results for OS favored regorafenib in all preplanned subgroup analyses. “We have seen a consistent benefit,” he said.

Bruix said the updated findings support the validity of analyzing outcomes by patterns of progression. In prior research, the development of new vascular invasion or extrahepatic spread has emerged as a significant predictor of a worse survival.

The new data show that patients who developed new extrahepatic lesions during sorafenib therapy had a longer probability of postprogression survival (PPS) with second-line regorafenib than with placebo. The median PPS for patients with new extrahepatic lesions on sorafenib was 10.6 months (95% CI, 8.4-12.3) with regorafenib versus 8.2 months (95% CI, 5.9-10.0) with placebo (HR, 0.66; 95%CI, 0.50-0.89). For those without new extrahepatic lesions during prior sorafenib, the median PPS was 14.1 months (12.3-15.7) on regorafenib versus 10.6 months (95% CI, 9.5-12.8) with placebo (HR, 0.67; 95% CI, 0.52-0.85).

In response to a question from an audience member, Bruix said investigators had tested many potential targets for biomarkers but these efforts have not yet yielded actionable data. “There are suggestions of all sorts but there is nothing that is robust,” he said.

Biopsies were not required for entry when RESORCE was launched in 2013, so investigators are confined to testing with blood samples, Bruix said.

Bruix J, Merle P, Granito A, et al. Overall survival (OS) update: 2-year follow-up from the phase 3 RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) progressing on sorafenib. Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16; London, England. O-023. ilca2018.org/wp-content/uploads/2018/08/ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf.

Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [erratum in 2017;389(10064):36. doi: 10.1016/S0140-6736(16)32615-0]. Lancet. 2017;389;10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.

Regorafenib Sustains OS Benefit in RESOURCE Trial Update

Regorafenib (Stivarga) maintained a prolonged overall survival (OS) benefit as second-line therapy for patients with advanced hepatocellular carcinoma (HCC) in a 2-year updated analysis of key findings from the pivotal RESORCE trial.

Regorafenib Sustains OS Benefit in RESORCE Trial Update

In a major advance that set a new standard of care for the treatment of patients with resected pancreatic cancer, a modified FOLFIRINOX regimen (mFOLFIRINOX) dramatically improved survival compared with standard gemcitabine as postoperative therapy. 

Findings from the PRODIGE 24/CCTG PA.6 study showed that with mFOLFIRINOX median overall survival (OS) was nearly 20 months longer than with gemcitabine: 54.4 versus 35.0 months, which represents a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.48-0.86; 

 The median disease-free survival (DFS) was 8.8 months longer with mFOLFIRINOX than with gemcitabine.

Researchers reporting the findings at the 2018 ASCO Annual Meeting said that mFOLFIRINOX should be the new adjuvant standard of care for those who are fit enough to undergo the chemotherapy combination after surgery.

“The gemcitabine arm is better than in every previous trial but the median [overall] survival we got with the FOLFIRINOX regimen is the best ever achieved in any previous adjuvant treatment,” said lead author Thierry Conroy, MD, a medical oncologist and director of the Institut de Cancerologie de Lorraine in Nancy, France, when discussing the findings during a press conference.

“FOLFIRINOX was more toxic than gemcitabine, but it’s still a safe regimen with manageable toxicities,” he said. “The FOLFIRINOX regimen should be considered the new standard of care after pancreatic cancer resection in patients with good performance status.”

The findings represent “an important significant improvement in overall survival for a notoriously aggressive disease,” said Andrew S. Epstein, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, who was serving as an ASCO expert. He noted, however, that patients should have a good performance status to be considered for mFOLFIRINOX.

“It would be tempting to give this regimen to anyone after pancreas cancer surgery, but because FOLFIRINOX is a relatively challenging regimen and, as we see, [there are] more toxicities from it compared with single-agent gemcitabine, we need to make sure that we recommend this regimen in the appropriate people—people who are healthy enough to withstand the rigorousness of the regimen.”

The PRODIGE 24/CCTG PA.6 study involved 493 patients with nonmetastatic pancreatic ductal adenocarcinoma treated at 77 French and Canadian centers from April 2012 to October 2016. It was conducted through Unicancer, a network of comprehensive cancer centers in France and a leading clinical trial sponsor in Europe.

To be eligible, patients were required to undergo surgery and have no tumor residue on a postoperative CT scan. Participants had to be between the ages of 18 and 79 years with World Health Organization performance status scores of ≤1.

Three to 12 weeks after surgery, participants were randomized 1:1 to receive mFOLFIRINOX or gemcitabine for 6 months. The mFOLFIRINOX regimen consisted of oxaliplatin, leucovorin, and irinotecan administered intravenously (IV) at day 1, followed by 5-fluorouracil via continuous IV infusion over 46 hours, for 12 two-week cycles. Gemcitabine was administered via IV on days 1, 8, and 15 every 28 days for 6 cycles.

The value of postoperative chemotherapy with gemcitabine and/or fluoropyrimidine for patients with pancreatic cancer has been established for 10 years, Conroy said. Nevertheless, most patients still relapse within 2 years.

In 2011, Conroy and colleagues demonstrated that FOLFIRINOX is more effective than single-agent gemcitabine as a first-line treatment in the metastatic setting for patients with pancreatic cancer and a good performance status.

 However, Conroy said the toxicities associated with that regimen made it a difficult choice for adjuvant therapy. Instead, investigators designed the trial with mFOLFIRINOX, which does not include bolus IV 5-fluorouracil and is therefore less likely to result in hematologic toxicities and excessive diarrhea.

The primary endpoint of the PRODIGE 24/CCTG PA.6 study was DFS. After a median follow-up of 33.6 months, patients who received mFOLFIRINOX had a median DFS of 21.6 months compared with 12.8 months with gemcitabine (HR, 0.58; 95% CI, 0.46-0.73; 

 <.001). The 3-year DFS was 39.7% with mFOLFIRINOX and 21.4% with gemcitabine.

In addition to improved median OS, a secondary endpoint of the study, mFOLFIRINOX demonstrated a superior OS rate (63.4% vs 48.6%) and cancer-specific survival rate (66.2% vs 51.2%) compared with gemcitabine at 3 years.

In terms of safety signals, mFOLFIRINOX resulted in higher rates of grade 3 or 4 adverse events (AEs) than gemcitabine, respectively, for diarrhea (18.6 vs 3.7%), fatigue (11.0% vs 4.6%), vomiting (5.0% vs 1.2%), and mucositis (2.5% vs 0%). There also was a 9.3% rate of grade 3/4 sensory peripheral neuropathy.

In the gemcitabine arm, the rate of grade 3/4 AEs was higher for thrombocytopenia (4.5% vs 1.3%) and febrile neutropenia (3.7% vs 2.9%). Patients treated with gemcitabine also experienced significantly higher rates of grades 1 to 4 headache, fever, flu-like symptoms, lymphopenia, and transaminase increases. There was 1 toxic death in the gemcitabine arm, Conroy said.

Although the findings show a significant benefit with mFOLFIRINOX, Conroy said single-agent gemcitabine remains an option for patients who have poor performance status scores 12 weeks after surgery, and in those with clear contraindications to the regimen.

Epstein said that the decision would hinge on a patient’s comorbidities. For example, if a patient has neuropathy, he may consider the combination of gemcitabine and capecitabine (Xeloda), which was validated for this population in the ESPAC-4 study last year.

Schilsky said most patients with pancreatic cancer who undergo surgery are likely candidates for mFOLFIRINOX. “These are patients who were fit enough to undergo surgery. This is not a simple surgery in patients with pancreatic cancer. The likelihood is that unless they have significant postoperative complications, if they are fit enough to undergo the surgery they’re ultimately going to be fit enough to get the FOLFIRINOX chemotherapy within 12 weeks after the surgery.”

Next steps for the research include exploring whether mFOLFIRINOX would be beneficial to patients before surgery.

Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA4001. meetinglibrary.asco.org/record/159164/abstract.

Conroy T, Desseigne F, Ychou M, et al; Groupe Tumeurs Digestives of Unicancer and PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. 

. 2011;364(19):1817-1825. doi: 10.1056/NEJMoa1011923.

Mahaseth H, Brutcher E, Kauh J, et al. Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma. 

. 2013;42(8):1311-1315. doi: 10.1097/MPA.0b013e31829e2006.

Neoptolemos JP, Palmer DH, Ghaneh P, et al; European Study Group for Pancreatic Cancer. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. 

. 2017;389(10073):1011-1024. doi: 10.1016/S0140-6736(16)32409-6.

Four-Drug Chemo Combo Significantly Improves Pancreatic Cancer Survival

Aromatase inhibitor (AI) therapy may pose a risk of cardiovascular disease to postmenopausal women with early-stage breast cancer, raising the possibility of a long-term complication in an era of growing survivorship when patients are treated with estrogen-targeting drugs for years, researchers said at the 2016 San Antonio Breast Cancer Symposium.

Women with locally advanced, estrogen receptor (ER)—positive breast cancer who received an AI as part of their treatment demonstrated reduced endothelial function, a predictor of cardiovascular disease, compared with healthy women in a small study conducted at the University of Minnesota.

Investigators found that the breast cancer survivors (n = 36) had significantly reduced large artery elasticity (LAE) and small artery elasticity (SAE) compared with the control group (n = 20). The women who had cancer also had a lower ratio on the EndoPAT test, which measures arterial function digitally.

Lead study author Anne H. Blaes, MD, MS, described the findings against a backdrop of concern about cardiovascular problems associated with breast cancer treatment. “Most women with early-stage breast cancer are at a greater risk of dying from cardiovascular disease than their breast cancer,” said Blaes, an associate professor in hematology and oncology at the University of Minnesota.

Although data are not collected consistently across studies, the incidence of cardiac events in adjuvant AI clinical trials ranges from 3% to 17%, Blaes said at a press conference where she discussed the study results. AI therapy has been associated with higher rates of hypertension, hypercholesterolemia, angina pectoris, and ischemic cardiovascular disease, the research team said in the study abstract.

Blaes said the findings point to another factor that women should ponder when weighing their therapy choices, including tamoxifen. “When we talk about prolonged endocrine therapy with aromatase inhibitors, we need to take into consideration the potential risks associated with that when we’re not seeing overall survival advantages,” Blaes said.

AI therapy reduces breast cancer-related mortality in women with operable ER-positive disease, and recent research has suggested that taking AIs for as long as 10 years could lower the risk of recurrence. However, the optimal use of AI therapy versus tamoxifen as a means of attacking estrogen production is a more complex question.

A meta-analysis of data on nearly 32,000 postmenopausal women found that AIs significantly reduced recurrence rates compared with tamoxifen but that the relative impact of the 2 drugs on all-cause mortality and breast cancer mortality differed depending upon the years of the treatment timeline in which they were taken and how they were sequenced.

Blaes stressed that researchers are not advising patients to refrain from taking AIs. She said that more research into the question is needed, including studies into the impact of AI therapy on women with a pre-existing diagnosis of cardiovascular disease.

C. Kent Osborne, MD, who served as moderator at the press conference, said the potential cardiovascular risk from AI treatment was “small,” but had not been fully evaluated compared with tamoxifen hormonal therapy.

“It doesn’t show up in most studies as death from myocardial infarction in aromatase inhibitor—treated patients versus tamoxifen,” said Osborne, who is the director of the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston.

In the Minnesota study, researchers recruited participants without the known cardiac risk factors of tobacco use, hypertension, or hyperlipidemia. More than 90% of the women were Caucasian and did not have a personal history of heart disease.

The breast cancer survivors had an average age of 61 years, a body mass index (BMI) of 27, and a mean systolic blood pressure (SBP) of 128.6 mmHg. The control group was slightly younger with an average age of 59 years, and the participants had a BMI of 26 and a mean SBP of 116 mmHg.

Most of the women in the breast cancer group had stage 1 or 2 disease; about half had received chemotherapy and two-thirds had been treated with radiation. For hormonal therapy, most of the women were taking anastrozole or letrozole and 7 had received prior tamoxifen.

For the endothelial function measures, the median LAE (ml/mmHg x 10) was 12.9 for the breast cancer survivors and 14.6 for the control group (

 = .12), and the median SAE (ml/mmHg x 10) was 5.2 for the survivors versus 7.0 for the control arm (

These values translated into an EndoPAT ratio of 0.8 for the breast cancer survivors and 2.7 for the control group (

 <.0001). An EndoPAT ratio of <1.67 has been associated with an increased risk of major cardiac events on a prior study, Blaes said.

Blaes said there were no differences in potential risk associated with whether the participants had received chemotherapy or radiation therapy, or whether their tumors were in the right or left side. However, the use of anastrozole was associated with a significant reduction in LAE compared with exemestane and letrozole (

= .03). There was no correlation found between the length of time on AI therapy and the EndoPAT ratio.

According to a recent study, postmenopausal women with early-stage breast cancer may be at risk of cardiovascular disease from aromatase inhibitor therapy.

Small Study Finds Risk of Cardiac Events With Adjuvant AI Therapy

Researchers in France have found that patients with lung cancer who used a web-based app to report and track their symptoms achieved impressive gains in survival compared with individuals who were followed using standard protocols.

The MoovCare system made a difference for patients because it resulted in early detection of dangerous conditions or recurrences, resulting in healthier individuals who were better able to undergo optimal therapy and earlier supportive care that improved quality of life, said lead study author Fabrice Denis, MD, PhD, during press briefing at the 2016 ASCO Annual Meeting.

Median overall survival (OS) for patients who used the MoovCare system was 19 months compared with 12 months for participants in the control group (HR, 0.325; 

= .0025), after 20 months of follow-up. Additionally, 75% of the patients followed through MoovCare were still alive at 1 year versus 49% with standard procedures.

A 50% reduction in the average number of imaging tests per patient per year was achieved with use of the app, said Denis, a researcher at the Institut Inter-regional de Cancérologie Jean Bernard in Le Mans, France.

MoovCare consists of a software application that patients or their caregiver use to report their symptoms. The algorithm analyzes the information for signals of potential relapse or complications and, if necessary, notifies the oncology care provider via email. The app can be accessed on mobile and desktop devices.

The improvements were achieved even though the relapse rates were similar for both groups—49% among those who used the app and 51% among those with typical follow-up, researchers reported.

However, performance scores stayed higher among patients who used MoovCare. As a result, 74% of these patients were able to undergo optimal therapy upon relapse compared with 33% who had not used the app (

Denis said the need for an app in lung cancer is particularly pressing. “There are no standard follow-ups to detect relapse in patients,” he said. “Relapses are frequent and often symptomatic … Symptomatic patients often wait, leading to health degradation and nonoptimal therapy.”

Denis and colleagues tested the system in a phase III trial conducted at 5 medical centers in France. Results were reported for 121 patients in the intent-to-treat analysis who were randomized to use either the MoovCare system (n = 60) or routine follow-up (n = 61). The trial was stopped early at the interim analysis because of the positive results.

The study population consisted of patients with nonprogressive non—small cell lung cancer or small cell lung cancer, stages IIA through IV. Participants were required to have a performance score of 0-2 and a symptomatic score <7. All patients underwent chemotherapy before starting the trial and were permitted to continue tyrosine kinase inhibitor therapy or maintenance therapy throughout the study.

Patients in the MoovCare arm were required to self-report weekly for 12 clinical symptoms including asthenia, cough, dyspnea, and anorexia. Those with stage II-IIIA cancers also received CT scans at 6-, 12-, and 24-month intervals whereas those with stage IIIB-IV cancers were scheduled for scans at 12 months and 24 months.

In the control arm, patients with stage II-IIIA cancers received scans every 6 months, while participants with stage IIIB-IV disease were scheduled for monthly scans starting at 3 months.

Additional CT scans could be performed at the investigator’s discretion for patients in both arms, Denis said.

In response to questions about MoovCare’s practicality, Denis said the system is easy to install on a computer and would simply require a doctor or nurse to monitor the emails.

However, Patricia Ganz, MD, an ASCO Expert in breast cancer who served as moderator for the press conference, said drawing benefit from such a system would necessitate changes in US practices. She said that similar experiments in the United States had found that information patients submit electronically does not generate action because of the cost of deploying personnel to monitor the data.

“We’re trying to restructure how we deliver care so that we can be responsive to these kinds of changes and these tools where patients can report their symptoms and how they’re doing on a regular basis,” said Ganz. “If there’s staff in the office who can respond [it would] really make a difference in preventing emergency room visits, hospitalizations, and so forth.”

ASCO spokesman Gregory A. Masters, MD, said the MoovCare system presents “one way to engage patients and allow them to take a more active role in their care.”

He said this is particularly important in lung cancer. “Lung cancer is a unique cancer in some ways because many of these patients have a lot of guilt about their diagnosis,” said Masters. “I think we see that more in lung cancer patients than in many other patients. Some patients don’t want to bother the doctor or the nurse or the healthcare team with their symptoms or they think [their symptoms] are not important.”

Sivan Innovation, an e-health company headquartered in Jerusalem that developed MoovCare, said the system is the first web application based on telemonitoring. The company said it would seek regulatory approvals for marketing it as a medical device.

The company also said it would start rolling out the application in France in 2017, and then elsewhere in Europe, the United States, Israel, and other countries. MoovCare also is in development for approximately 15 other cancer indications, notably lymphoma, in a partnership with Takeda France, the company said.

 Denis F, Lethrosne C, Pourel N, et al. Overall survival in patients with lung cancer using a web-application-guided follow-up compared to standard modalities: results of phase III randomized trial. 

Lung Cancer Survival Improved in Patients Who Used a Web App to Report Symptoms

The 3-year survival rate of patients with advanced melanoma treated with pembrolizumab (Keytruda) has reached 40%, with many responders in remission even after stopping treatment.

The results from the KEYNOTE-001 study, which were presented during a presscast held in advance of the 2016 ASCO Annual Meeting, showed that 15% of the patients experienced complete remissions according to immune-related criteria (irRC) after taking the PD-1 inhibitor and that nearly 90% of these responders remain in remission. The median overall survival (OS) was 24.2 years.

The findings are raising hopes that PD-1 checkpoint blockade immunotherapies can deliver a cure for patients with the disease, researchers said during the presscast.

“These long-term data support the durable benefit of pembrolizumab and confirm its use as one of the new standards of care for patients with advanced melanoma,” said lead study author Caroline Robert, MD, PhD, head of the Dermatology Unit at the Institut Gustave-Roussy in Paris.

Robert said the results are particularly noteworthy considering that median OS for patients with advanced melanoma was less than 1 year before the introduction of checkpoint blockade immunotherapies, starting with the anti-CTLA—4 antibody ipilimumab (Yervoy) in 2011.

“It’s incredibly encouraging that we could potentially see a cure in melanoma as evidenced by the very prolonged response rate and the durability of this response,” Don S. Dizon, MD, FACP, an ASCO spokesperson who served as moderator of the presscast, said in reference to the pembrolizumab data.

The FDA granted pembrolizumab an accelerated approval in melanoma in September 2014 based on response rates among a cohort of patients in the KEYNOTE-001 study. The long-term results that will be presented at ASCO this year represent the largest dataset for survival statistics for pembrolizumab, Dizon said.

The PD-1 inhibitor nivolumab (Opdivo) demonstrated a robust 5-year OS rate of 34% for heavily pretreated patients with metastatic melanoma who had not received prior ipilimumab, according to long-term findings from a single-arm phase I study presented at the 2016 AACR Annual Meeting.

Robert, however, noted that the nivolumab trial included results for 107 patients, whereas the enrollment in KEYNOTE-001 was far higher. Median follow-up in KEYNOTE-001 was 32 months.

The phase Ib KEYNOTE-001 enrolled 655 patients with newly diagnosed and previously treated melanoma between December 2001 and September 2013. Seventy-five percent of the participants had received prior treatment including ipilimumab.

Participants were randomized to receive pembrolizumab at 1 of 3 dosing levels: 2 mg/kg or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Investigators determined that the optimal dose is 2 mg/kg via intravenous infusion every 3 weeks, and that is the dosing that the FDA has recommended.

The average duration of treatment was approximately 1 year. Some patients received pembrolizumab for more than 3.5 years and 18 participants are still taking the drug, Robert said.

The overall response rate was 33% by RECIST criteria including 95 patients who had a complete response (CR) by irRC. Of these patients, 61 stopped treatment after achieving a CR following a median treatment duration of 23 months. “The vast majority of them are still without treatment and [have] a complete response,” Robert said.

Overall, 73% of the responders experienced a response duration of ≥2 years, and the median duration of response was not reached. For those who reached a CR, the duration of response ranged from >17 months to >43 months.

Two patients experienced disease progression after stopping pembrolizumab treatment, and 1 of those patients has started another course of therapy with the drug with the outcome not yet known, Robert said.

The toxicity profile of pembrolizumab was manageable, and there were no new safety signals or surprises, according to Robert. She said 8% of the patients stopped treatment because of adverse events (AEs) but that there were no fatalities related to the drug. The most common AEs were fatigue (40%), itchiness (28%), and rash (23%).

Pembrolizumab also demonstrated a survival advantage in the phase III KEYNOTE-006 trial, which compared 2 pembrolizumab regimens with ipilimumab. The 1-year OS rates for the pembrolizumab arms were 74.1% and 68.4% for 10 mg/kg every 2 weeks and 3 mg/kg every 3 weeks, respectively, compared with 58.2% for ipilimumab.

In addition to melanoma, pembrolizumab is approved for patients with non—small cell lung cancer and is under study in more than 12 additional tumor types including head and neck, bladder, breast, and colorectal cancers.

Robert C, Ribas A, Hamid O, et al. 3-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. 

Hodi SF, Kluger HM, Sznol M, et al. Durable, long-term survival in previously treated patients with advanced melanoma who received nivolumab monotherapy in a phase I trial. Presented at the 2016 AACR Annual Meeting; April 16-20, New Orleans, Louisiana. Abstract CT001.

Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. 

Pembrolizumab Reaches 40% Three-Year Survival Rate in Melanoma

Can a physically fit twenty-something who never smoked a cigarette get lethal lung cancer? Unfortunately, the answer is yes, and doctors don’t really know why.

But if Bonnie Addario has anything to say about it, those answers won’t be cloaked in mystery much longer.

Unraveling genetic reasons for lung cancers that strike people under the age of 40 has become one of the research passions of the Bonnie J. Addario Lung Cancer Foundation. Addario, whose own battle with lung cancer started when she was in her 50s, turned her attention to the problems faced by younger patients about 5 years ago when she received a phone call from a distraught mother searching for help for her 21-year-old daughter.

The young woman, Jill Costello, was a member of her college rowing team who had never been a smoker, yet she had just been diagnosed with stage IV lung cancer. She died just 1 year later in June 2010, shortly after graduating from the University of California, Berkeley and leading its women’s rowing team to PAC-10 and NCAA championships.

Addario, who has cultivated a network of the world’s top lung cancer researchers since forming her foundation in 2006, tried to help.

“We did everything we could for her,” Addario recalls. “We literally reached out to everyone in the United States and around the world and nobody had any answers.”

After the foundation itself and Jill’s friends took steps to increase awareness about lung cancer among younger people, Addario started hearing from other young, athletically fit never-smokers who had the disease. 

Statistics show why it’s so difficult to put such younger patients on the research radar. Lung cancer in the United States is most frequently diagnosed among people aged 65 to 74 years, according to the National Cancer Institute. Fewer than 2% of cases are found in people under age 40.

Yet, lung cancer is so prevalent that even a small percentage of patients adds up to a large number of people, Addario notes. “If you look at 1.4 million people diagnosed around the world every year, 2% is a big number of patients,” she says.

The foundation started a group called Jill’s Legacy in her honor, to help raise money for young patients with lung cancer. And, the Addario Lung Cancer Medical Institute (ALCMI), which the foundation formed to conduct a variety of research into the disease, set out to determine the characteristics of lung cancer in younger people.

Tapping into the best minds in the field, ALCMI designed an innovative clinical trial to find patients under age 40 and analyze their tumors to see whether there have gene mutations that are different from those found in older people with lung cancer. Barbara J. Gitlitz, MD, from the University of Southern California and Geoffrey R. Oxnard, MD, from the Dana-Farber Cancer Institute are leading the study.

“We use social media to find people around the world,” says Addario. “People can enter the study without ever leaving home.” 

Participants are able to fill out medical history and consent forms online to be considered for the study. Study organizers then mail them a laboratory-approved kit they can take to their doctor, who collects tissue, blood, and plasma samples and ships the kit to US centers for analysis. If molecular diagnostics have never been conducted, the samples are sent to Foundation Medicine in Massachusetts, which tests the specimens free of charge.

The ongoing study has attracted 120 participants from the United States and Europe thus far, according to findings presented at the World Conference on Lung Cancer in September. Preliminary results show that more than 75% of the participants have a mutation that can be treated with a targeted therapy.

Meanwhile, ALCMI-funded researchers have detailed the results of a study examining the genomics of patients treated at Dana-Farber between January 2002 and December 2014 in 

. They found that younger patients are more likely than older people to have a targetable gene mutation and are less likely to have ever smoked. The findings indicate the importance of mutation testing for younger patients because drugs may be available to help them.

Addario believes that a shining a light on the nature of lung cancer among young people will help battle the stigma that accompanies the disease.

“I think they’re going to change the face of lung cancer,” she says of the young patients. “We’re starting to see people understanding that although smoking is a trigger for lung cancer—and many other cancers and heart disease&mdash;lung cancer was wrongly stigmatized for all these years and underfunded because of it.”

For more information about the Genomics of Young Lung Cancer study, visit their 

Younger Patients Are Changing the Face of Lung Cancer

Although many treatment options exist for women with ductal carcinoma in situ (DCIS), clinicians often must "guestimate” when it comes to determining the risk of recurrence for patients who choose breast-conserving surgery and how best to manage their care, according to Kimberly J. Van Zee, MS, MD.

In order to help clarify the decision-making process, Van Zee has developed a nomogram that calculates the risk of ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery.

Ten clinical and pathological variables are taken into account with the nomogram which then estimates a 5- and 10-year risk of recurrence in the same breast. These factors include the patient’s age at diagnosis, family history, prior adjuvant therapy, tumor grade, and surgical margins. The tool is available free of charge on Memorial Sloan Kettering Cancer Center’s (MSK) website (

The calculator is useful to clinicians and patients alike, said Van Zee, who is an attending surgeon at MSK and a professor of surgery at Weill Medical College of Cornell University. She discussed the nomogram in advance of her presentation on the topic at the 33rd Annual Miami Breast Cancer Conference, held March 13-16,2016.

The nomogram can help physicians and patients weigh the pros and cons of the many treatment options available for DCIS by estimating the risk associated with each option. Van Zee said she often sits with patients and plugs information into the calculator so that they can understand their own recurrence risks and treatment choices.

“I find that women are often very educated and they’ve done a lot of research. They come in with 20 pages of questions off the Internet and they really relish having some kind of number to compare their options,” said Van Zee. For patients who might not be as comfortable with numbers, Van Zee translates the predictive values into more understandable terms, for example, “1 in 10 women like you.”

Although serious adverse events from radiation in this treatment setting are rare, Van Zee believes the potential harms must be considered because there is no survival benefit from radiation of DCIS.

“In my practice, I try to help a woman weigh the risks and benefits of the various treatment options according to her own values,” said Van Zee. “One person may be very risk averse, both in terms of any treatment and any risk of recurrence. A mastectomy may be the best option for such a person. “On the other hand, there may be a woman who is very risk tolerant and chooses not to have radiation,” Van Zee said. “The nomogram will give her some estimate of her risk with that option so that she can assess if that risk is acceptable to her.”

To create the nomogram, Van Zee and colleagues looked at recurrences among 1868 patients who had undergone breast-conserving surgery for DCIS at MSK from 1991-2006.

 Van Zee chose 10 variables that have been correlated with recurrence risk in prior research: age at diagnosis, family history, initial presentation, nuclear grade, necrosis, margin status, number of excisions, year of surgery, radiation therapy, and endocrine therapy.

The calculator has since been validated in four external studies in different patient populations, most recently by researchers at Harvard Medical School and Kaiser Permanente, Van Zee said in a presentation at the ASTRO Annual Meeting in October 2015.

The studies calculated how well the nomogram performed in their populations, using a C-index.

The C-index in a perfect model is 1.0, according to Van Zee. The validation studies determined that the DCIS nomogram has a C-index ranging from 0.63 to 0.68, depending on the study, which compares favorably with several commercially available risk-assessment tools.2 Collins et al found that “the overall correlation between 10-year nomogram-predicted recurrences and observed recurrences was 0.95.”

Van Zee’s next step for the nomogram is to incorporate margin width for women who have undergone surgery for DCIS. She and colleagues have recently published an analysis of margin width and risk of recurrence of DCIS, and she hopes that incorporation of these findings will improve the predictive model even further.4

Rudloff U, Jacks LM, Goldberg JL, et al. Nomogram for predicting the risk of local recurrence after breast-conserving surgery for ductal carcinoma in situ. 

A nomogram calculates the risk of ipsilateral breast tumor recurrence after breast-conserving surgery.

Anita T. Shaffer