Staying up-to-date in the fast-paced world of oncology literature is a daunting task at best. To assist with that task, The ASCO Post has assembled an assortment of studies recently published in the Journal of Clinical Oncology. The topics range from therapy for stage IV non–small cell lung cancer to new targeted treatments for metastatic renal cell carcinoma, with highlights also provided on surveillance mammography for older breast cancer survivors, first-line treatment of metastatic castration-resistant prostate cancer, and imaging modalities for patients with multiple myeloma.
ASCO Guideline on Stage IV NSCLC Therapy Updated
An update of the ASCO clinical practice guideline on the systemic treatment of patients with stage IV non–small cell lung cancer (NSCLC) clarifies the role of immunotherapy in this setting. The update also provides new recommendations on the use of targeted therapies for patients with changes in tumor EGFR, ALK, and ROS1 genes.
“Treatment for lung cancer has become increasingly complex over the past several years. This guideline update provides oncologists with the tools to choose therapies that are most likely to benefit their patients,” said Nasser Hanna, MD, Co-Chair of the expert panel that developed the guideline update.
Treatment for lung cancer has become increasingly complex over the past several years.— Nasser Hanna, MD
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ASCO published the last guideline on systemic therapy for stage IV NSCLC in 2015. To develop this update, an expert panel with multidisciplinary representation reviewed medical literature published between February 2014 and December 2016. A total of 14 randomized controlled clinical trials provided the evidence base for the recommendations.
Our patients rely on us to keep up with the most effective and best tolerated therapies to help manage this devastating disease.— Gregory Masters, MD, FACP, FASCO
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“Our patients rely on us to keep up with the most effective and best tolerated therapies to help manage this devastating disease,” said Gregory Masters, MD, FACP, FASCO, Co-Chair of the expert panel that developed the guideline update. “Knowing when to use targeted therapies or immunotherapy in place of more toxic chemotherapy can help improve the quality of life of our patients.”
First-Line Therapy Recommendations
For patients with EGFR mutation–negative, ALK rearrangement–negative, and ROS1 rearrangement–negative tumors:
For patients with EGFR mutation-–positive, ALK rearrangement–positive, or ROS1 rearrangement–positive tumors:
Second-Line Therapy Recommendations
Surveillance Mammography by Life Expectancy in Older Breast Cancer Survivors
Rachel A. Freedman, MD, MPH, of the Dana-Farber Cancer Institute, and colleagues found that many older breast cancer survivors with a limited life expectancy still undergo annual surveillance mammography despite the absence of known benefits.
Rachel A. Freedman, MD, MPH
The study involved analysis of National Health Interview Study data from 2000, 2005, 2008, 2010, 2013, and 2015 to determine surveillance mammography use among women aged ≥ 65 years with a history of breast cancer. Of 1,040 patients identified, 33.7% were aged ≥ 80 years, 88.6% were white, 8.6% had an estimated life expectancy of ≤ 5 years, and 35.1% had an estimated life expectancy of ≤ 10 years.
Surveillance Rates by Life Expectancy
In total, 78.9% of patients reported routine surveillance mammography in the prior 12 months. Decreasing life expectancy was associated with a reduced likelihood of mammography (P < .001 overall; odds ratios of 0.4 and 0.4 for a life expectancy of ≤ 5 and ≤ 10 years vs a greater life expectancy in adjusted analysis). However, mammography within the prior year was still reported by 56.7% of those with a life expectancy ≤ 5 years and 65.9% of those with a life expectancy ≤ 10 years. No recent surveillance mammography was reported by 14.1% of patients with a life expectancy > 10 years.
The investigators concluded: “Many (57%) older breast cancer survivors with an estimated short life expectancy (≤ 5 years) receive annual surveillance mammography despite unknown benefits, whereas 14% with an estimated life expectancy > 10 years did not report mammography. Practice guidelines are needed to optimize and tailor follow-up care for older patients.”
First-Line Cabazitaxel vs Docetaxel in Metastatic Castration-Resistant Prostate Cancer
The phase III FIRSTANA trial has shown no difference in overall survival with two dose regimens of cabazitaxel (Jevtana) vs docetaxel in the first-line treatment of metastatic castration-resistant prostate cancer. Results were reported by Stéphane Oudard, MD, PhD, of René Descartes University, and colleagues. Cabazitaxel is currently approved with prednisone for treatment of hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.
In the open-label trial, 1,168 men from 159 sites in 25 countries were randomized between May 2011 and October 2013 to receive cabazitaxel at 20 mg/m2 (n = 389), cabazitaxel at 25 mg/m2 (n = 388), or docetaxel at 75 mg/m2 intravenously (n = 391) once every 3 weeks plus oral prednisone at 10 mg daily. The primary endpoint was overall survival.
Overall Survival and Toxicity
[Two different regimens of cabazitaxel] did not demonstrate superiority for overall survival vs docetaxel in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.— Stéphane Oudard, MD, PhD, and colleagues
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Median overall survival was 24.5 months in the cabazitaxel 20 mg/m2 group (hazard ratio [HR] vs docetaxel = 1.01, P = .997), 25.2 months in the cabazitaxel 25 mg/m2 group (HR vs docetaxel = 0.97, P = .757), and 24.3 months in the docetaxel group. Composite median progression-free survival was 4.4 months (HR = 1.06, P = .422), 5.1 months (HR = 0.99, P = .804), and 5.3 months, respectively.
The radiographic tumor response rate (32.4% in cabazitaxel 20 mg/m2 group) was higher in the cabazitaxel 25 mg/m2 group vs the docetaxel group (41.6% vs 30.9%, nominal P = .037, without multiplicity test adjustment). No significant differences among the groups were observed for tumor or prostate-specific antigen progression-free survival; pain progression-free survival was better in the docetaxel group than in the cabazitaxel 25 mg/m2 group (HR = 1.19, P = .035).
Grade 3 or 4 treatment-related adverse events occurred in 41.2%, 60.1%, and 46.0% in the 3 groups, respectively. Any-grade treatment-related febrile neutropenia (12% [2% with lower-dose cabazitaxel] vs 8%), diarrhea (50% [33%] vs 37%), and hematuria (25% [20%] vs 4%) were more common with cabazitaxel at 25 mg/m2, whereas peripheral neuropathy (25% vs 12% [12%]), peripheral edema (20% vs 8% [10%]), alopecia (39% vs 13% [9%]), and nail disorders (9% vs 1% [< 1%]) were more common with docetaxel. Treatment was discontinued due to adverse events in 25.2%, 31.7%, and 33.9% of patients, respectively.
The investigators concluded: “[Cabazitaxel at 20 mg/m2 and cabazitaxel at 25 mg/m2] did not demonstrate superiority for [overall survival] versus [docetaxel at 75 mg/m2] in patients with chemotherapy-naive [metastatic castration-resistant prostate cancer]. Tumor response was numerically higher with [cabazitaxel at 25 mg/m2] versus [docetaxel]; pain [progression-free survival] was numerically improved with [docetaxel] versus [cabazitaxel at 25 mg/m2]. Cabazitaxel and docetaxel demonstrated different toxicity profiles, with overall less toxicity with [cabazitaxel at 20 mg/m2].”
Comparison of MRI vs PET-CT in Multiple Myeloma
A study reported by Philippe Moreau, MD, of the University Hospital Hôtel-Dieu, Nantes, and colleagues indicated no difference between magnetic resonance imaging (MRI) and positron-emission tomography–computed tomography (PET-CT) in detecting bone lesions at diagnosis in patients with multiple myeloma. PET-CT normalization after induction therapy and prior to maintenance therapy was associated with improved outcome.
There is no difference in the detection of bone lesions at diagnosis when comparing PET-CT and MRI.— Philippe Moreau, MD
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Patients in the IMAJEM study were a subgroup of 134 patients from French centers involved in the international IFM/DFCI 2009 study assessing the front-line combination of eight cycles of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) vs RVD plus autologous stem cell transplantation, followed by lenalidomide maintenance. In this subgroup, [18F]fluorodeoxyglucose PET-CT and MRI were performed at diagnosis, after three cycles of RVD, and before maintenance therapy. The primary endpoint was the detection of bone lesions at diagnosis.
Detection of Bone Lesions and Prognostic Ability
Results at diagnosis were positive on MRI in 127 patients (95%) and on PET-CT in 122 patients (91%; P = .33). Normalization of MRI after three cycles of RVD and before maintenance was not predictive of progression-free or overall survival. PET-CT became normal after three cycles of RVD in 32% of the patients; this group had a trend toward improved 30-month progression-free survival vs those without normalization (78.7% vs 56.8%, P = .08), with no significant effect of normalization observed for overall survival. PET-CT normalization before maintenance was observed in 62% of patients, with these patients having improved 2-year progression-free survival (72.0% vs 56.8%, P = .011) and overall survival (94.2% vs 72.9%, P = .033).
On multivariate analysis, extramedullary disease at diagnosis was an independent prognostic factor for progression-free and overall survival, and PET-CT normalization before maintenance was an independent prognostic factor for progression-free survival (P < .001).
The investigators concluded: “There is no difference in the detection of bone lesions at diagnosis when comparing PET-CT and MRI. PET-CT is a powerful tool to evaluate the prognosis of de novo myeloma.”
Nivolumab Plus Ipilimumab in Metastatic Renal Cell Carcinoma
The phase I CheckMate 016 trial has shown activity of the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) in metastatic renal cell carcinoma. These findings were reported by Hans J. Hammers, MD, PhD, of The University of Texas Southwestern Medical Center, and colleagues.
In the dose-escalation study, patients were randomized to three nivolumab/ipilimumab combination groups and two nivolumab plus tyrosine kinase inhibitor groups. The current report is confined to the nivolumab/ipilimumab groups.
Hans J. Hammers, MD, PhD
Patients received nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (N3I1 group, n = 47), nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (N1I3 group, n = 47), or nivolumab at 3 mg/kg plus ipilimumab at 3 mg/kg (N3I3 group, n = 6) every 3 weeks for 4 doses followed by nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or dose-limiting toxicity. All six patients in the N3I3 arm (n = 6) were censored at the time of analysis due to dose-limiting toxicity or other reasons. Overall, 53% and 45% of the N3I1 and N1I3 patients were treatment-naive, respectively.
Combination Activity and Adverse Events
At a median follow-up of 22.3 months, confirmed objective response was observed in 40.4% of both groups, with responses ongoing at last analysis in 42.1% of the responders in the N3I1 group and 36.1% in the N1I3 group. Response rates for previously treated and treatment-naive patients were 45.5% and 36.0% in the N3I1 group and 38.5% and 42.9% in the N1I3 group. Progression-free survival at 1 year was 40.0% and 46.4%. Overall survival at 2 years was 67.3% and 69.6%.
Grade 3 or 4 treatment-related adverse events were reported in 38% of the N3I1 group and in 62% of the N1I3 group. The most common events were increased lipase (15%) in the N3I1 group and increased lipase (28%), increased alanine transaminase (21%), diarrhea (15%), colitis (15%), and increased aspartate transaminase (13%) in the N1I3 group.
The investigators concluded: “Nivolumab plus ipilimumab therapy demonstrated manageable safety, notable antitumor activity, and durable responses with promising [overall survival] in patients with [metastatic renal cell carcinoma].”
Noninferior Outcome With Ado-trastuzu-mab Emtansine vs Trastuzumab Plus Taxane in HER2-Positive Advanced Breast Cancer
In the phase III MARIANNE trial, Edith A. Perez, MD, of Mayo Clinic, Jacksonville, Florida, and colleagues found that ado-trastuzumab emtansine (Kadcyla) was associated with noninferior progression-free survival compared with trastuzumab (Herceptin) plus taxane in patients with HER2-positive advanced breast cancer who had received no prior therapy for advanced disease.
Tolerability was improved with ado-trastuzumab emtansine. Ado-trastuzumab emtansine plus pertuzumab (Perjeta) was also noninferior to trastuzumab-taxane, with no difference found between ado-trastuzumab emtansine and ado-trastuzumab emtansine plus pertuzumab. Updated data from the trial were presented earlier this year at the ASCO Annual Meeting.
In the trial, 1,095 patients from 241 sites in 38 countries were randomized 1:1:1 between July 2010 and May 2012 to receive trastuzumab plus taxane (n = 365), ado-trastuzumab emtansine (n = 367), or ado-trastuzumab emtansine plus pertuzumab (n = 363). In the trastuzumab-taxane control group, 257 patients received docetaxel and 96 received paclitaxel.
[Ado-trastuzumab emtansine] showed noninferior, but not superior, efficacy and better tolerability than did taxane plus trastuzumab for first-line treatment of HER2-positive, advanced breast cancer.— Edith A. Perez, MD, and colleagues
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Trastuzumab was given at an 8-mg/kg loading dose followed by 6 mg/kg for subsequent cycles with docetaxel and at a 4-mg/kg loading dose followed by 2 mg/kg for subsequent weeks with paclitaxel. Docetaxel was given at 75 or 100 mg/m2 every 3 weeks and paclitaxel was given at 80 mg/m2 weekly for a minimum of 6 cycles (18 weeks) until disease progression or unacceptable toxicity. Ado-trastuzumab emtansine was given at 3.6 mg/kg every 3 weeks and pertuzumab was given at an 840-mg loading dose followed by 420 mg every 3 weeks for subsequent cycles.
Stratification factors were world region, prior neoadjuvant or adjuvant therapy, and visceral disease. The primary endpoint was progression-free survival on independent review. The study was open label with regard to control group vs ado-trastuzumab emtansine–containing groups and blinded with regard to pertuzumab vs placebo in the ado-trastuzumab emtansine groups.
Across the treatment groups, the median age was 52 to 55 years. About 65% were white, and patients were from Asia, Western Europe, Canada, and the Australia/Pacific region. Virtually all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. More than half of the patients had estrogen receptor– or progesterone receptor–positive disease. Nearly half of patients had received no prior neoadjuvant or adjuvant therapy. Of those who had received prior therapy, about 30% were given HER2-directed treatment (trastuzumab or lapatinib [Tykerb]), between 29% and 36% were given taxane, between 42% and 46% were given anthracycline, and approximately 25% were given hormonal treatment.
Progression-Free Survival and Other Outcomes
The median follow-up was approximately 35 months in all three groups at the time the data were published. Median progression-free survival was 13.7 months in the control group vs 14.1 months in the ado-trastuzumab emtansine group (stratified hazard ratio [HR] = 0.91, 97.5% confidence interval [CI] = 0.73–1.13, P = .31, vs control) and 15.2 months in the ado-trastuzumab emtansine plus pertuzumab group (stratified HR = 0.87, 97.5% CI = 0.69–1.08, P = .14, vs control). Both experimental treatments met the noninferiority criterion vs control of the upper limit of the hazard ratio (97.5% CI below 1.18). No significant improvement was observed with ado-trastuzumab emtansine plus pertuzumab vs ado-trastuzumab emtansine (stratified HR = 0.91, 97.5% CI = 0.73–1.13). Demonstration of superiority would have required meeting the target hazard ratio of 0.75 for ado-trastuzumab emtansine–containing regimens vs control and 0.73 for comparison between ado-trastuzumab emtansine–containing regimens (with P value of ≤ .025).
Analysis in prespecified subgroups showed progression-free survival findings similar to overall outcomes. Trends favored ado-trastuzumab emtansine vs control in patients who had received previous neoadjuvant or adjuvant therapy with trastuzumab or lapatinib (HR = 0.75; HR for no prior treatment = 1.12) and in patients who had received prior taxane (HR = 0.69; HR for no prior taxane = 1.10). No notable subgroup differences were observed between ado-trastuzumab emtansine and ado-trastuzumab emtansine plus pertuzumab.
Response rates were 67.9% in the control group, 59.7% with ado-trastuzumab emtansine, and 64.2% with ado-trastuzumab emtansine plus pertuzumab. Median response durations were 12.5, 20.7, and 21.2 months, respectively. In the first interim overall survival analysis, median overall survival had not been reached in any treatment group.
Grade ≥ 3 adverse events occurred in 54.1% of the control group, 45.4% of the ado-trastuzumab emtansine group, and 46.2% of the ado-trastuzumab emtansine plus pertuzumab group; the most commonly reported adverse events were neutropenia (19.8%), febrile neutropenia (6.5%), and diarrhea (4.2%) in the control group; increased aspartate transaminase (6.6%), thrombocytopenia (6.4%), and anemia (4.7%) in the ado-trastuzumab emtansine group; and thrombocytopenia (7.9%), anemia (6.0%), and increased alanine transaminase (5.2%) in the ado-trastuzumab emtansine plus pertuzumab group.
The most common adverse events of any grade with a 5% difference in incidence between the control and ado-trastuzumab emtansine groups were alopecia (59.8%), diarrhea (48.7%), and nausea (37.1%) in the control group; nausea (47.1%), headache (32.1%), and epistaxis (31.0%) in the ado-trastuzumab emtansine group; and nausea (52.2%), diarrhea (48.1%), and epistaxis (34.7%) in the ado-trastuzumab emtansine plus pertuzumab group.
Left ventricular ejection fraction of < 50% with a ≥ 15 percentage point decrease from baseline was observed in 4.5% of the control group, 0.8% of the ado-trastuzumab emtansine group, and 2.5% of the ado-trastuzumab emtansine plus pertuzumab group. Adverse events led to treatment discontinuation in 29.7%, 18.3%, and 19.1% of patients, respectively. Adverse events led to death in 1.7%, 1.1%, and 1.9% of patients, respectively. The median time to a clinically meaningful decrease in health-related quality of life (on Functional Assessment of Cancer Therapy–Breast assessment) from baseline was 3.6 months in the control group, 7.7 months with ado-trastuzumab emtansine, and 9.0 months with ado-trastuzu-mab emtansine plus pertuzumab.
Updated Analysis and Overall Survival
Final results from the MARIANNE Study were presented by Carlos Barrios, MD, on behalf of Edith A. Perez, MD, and other study investigators earlier this year at the 2017 ASCO Annual Meeting.2 Dr. Barrios is Director of the Cancer Institute at the Hospital Mãe de Deu in Porto Alegre, Brazil. At the clinical cutoff date of May 15, 2016, median follow-up was 54 months and 512 patients had died. The median overall survival was 50.9, 53.7, and 51.8 months with patients receiving trastuzumab plus taxane, ado-trastuzumab emtansine, and ado-trastuzumab emtansine plus pertuzumab, respectively. Fewer grade ≥3 adverse events were reported in patients receiving ado-trastuzumab emtansine. The investigators concluded “With this longer follow-up, the [ado-trastuzumab emtansine] safety profile was consistent with the primary analysis and prior experience. While overall survival was similar across treatment arms, a median overall survival of 53.7 months and fewer grade ≥3 adverse events (vs other arms) supports [ado-trastuzumab emtansine] as an effective and tolerable alternative first-line treatment for patients with HER2-positive metastatic breast cancer.”