New Research Presented in Breast, Gastric, Esophageal Cancers, Melanoma, and Multiple Myeloma, plus Supportive Care 


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©ASCO/Todd Buchanan 2013

Attendees at the ASCO Annual Meeting are faced with a major challenge of trying to attend as many important sessions as they can over a 4-day period. Our challenge is to feature the major news in The ASCO Post. In addition to our regular comprehensive coverage of key presentations, the following selected highlights describe other noteworthy studies of interest.

BOLERO-3: mTOR Inhibition in Breast Cancer

The addition of everolimus (Afinitor) to therapy improved progression-free survival in patients with HER2-positive, trastuzumab (Herceptin)-resistant, taxane-pretreated advanced breast cancer in the BOLERO-3 trial.1 However, clinical benefit rates were not improved, suggesting that the overall benefit of this treatment approach may be less than striking.

Ruth O’Regan, MD, of Emory University School of Medicine, Atlanta, presented the results of ­BOLERO-3, which included 569 patients who received everolimus daily plus vinorelbine and trastuzumab weekly, or vinorelbine/trastuzumab alone. All had received prior taxane therapy, and 27% had received prior lapatinib (Tykerb).

The study met its primary endpoint. Everolimus improved median progression-free survival to 7.0 months, a small increase from 5.78 months with placebo (hazard ratio [HR] = .78; P = .0067). Subgroup analyses suggested the benefits were greatest among patients younger than age 65, those with hormone receptor–negative tumors, and those who had received prior adjuvant or neoadjuvant trastuzumab. Response rates and stable disease rates were not significantly different between the groups, and overall survival data were not mature.

Discussant Kimberly L. Blackwell, MD, of the Duke Cancer Institute, Durham, North Carolina, said the role for mTOR inhibition in this patient population remains unclear after the study. The lack of effect on overall survival (to date) or clinically meaningful outcomes makes it difficult to call for a change to the standard of care, despite the improvement in progression-free survival, she maintained. “There are other HER2-targeted agents that do provide a documented overall survival benefit,” including the combination of docetaxel, trastuzumab, and pertuzumab (Perjeta), Dr. Blackwell noted.

Lapatinib plus CapeOx in Gastric, Esophageal Cancer

In patients with HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma, the addition of lapatinib to CapeOx (capecitabine [Xeloda] plus oxaliplatin) failed to improve overall survival, the primary endpoint of the TRIO-013/LOGiC trial, presented by J. Randolph Hecht, MD, of the David Geffen School of Medicine at the University of California, Los Angeles.2

In the study of 545 patients, median overall survival was 12.2 months with lapatinib plus CapeOx, vs 10.5 months with CapeOx alone (HR .91; P = .35). Median progression-free survival was 6.0 vs 5.4 months, respectively (HR = .86; P = .10), though in an analysis that censored patients from the start of second-line therapy, a benefit was observed with the lapatinib-containing regimen (HR = .82; P = .04).

“In subgroup analyses, patients from Asia and those younger than age 60 experienced an increased effect from lapatinib,” Dr. Hecht added. The median overall survival in Asian patients improved from 10.9 months with CapeOx alone to 16.5 months with lapatinib added (HR = .68). In younger patients, median overall survival improved from 9.0 to 12.9 months (HR = .69). Serious adverse events were more common in the lapatinib-containing arm (27% vs 19%) as were fatal adverse events (6% vs 3%).

Early Transplant plus Maintenance in Multiple Myeloma

In patients with newly diagnosed multiple myeloma, treating with high-dose melphalan and autologous transplantation (MEL200), followed by maintenance therapy with lenalidomide (Revlimid), resulted in the best progression-free survival in a four-arm comparison reported by Antonio Palumbo, MD, of the University of Torino, Italy.3 In fact, each of the two components of this strategy was independently associated with improvement.

The trial randomly assigned 402 patients aged 65 or younger to the combination of melphalan, prednisone, and lenalidomide (MPR) or MEL200, and subsequently to maintenance with lenalidomide or no maintenance. Median progression-free survival was 38 months with MEL200 vs 24 months with MPR, with MEL200 providing an additional 14 months of remission (HR = 1.69; P < .0001). Overall survival was not different, but longer follow-up may be required, Dr. Palumbo suggested.

For the secondary randomization, response rates were similar whether patients received lenalidomide maintenance or not. However, patients receiving maintenance therapy had a significantly longer progression-free survival (37 vs 26 months: HR = .52; P < .0001) and, at 5 years, a difference in overall survival as well (75% vs 58%; HR = .62; P = .02).

Sagar Lonial, MD, of Emory University, who discussed the paper, commented, “It appears pretty clear from these data that the benefit of high-dose therapy and autologous transplant is clear and, in my mind, the benefit of maintenance post–autologous transplant is also very clear. We now have two trials demonstrating a significant improvement in overall survival.”

Lambrolizumab in Melanoma

Half of advanced melanoma patients receiving lambrolizumab at its optimal dose responded to the anti-PD-1 monoclonal antibody in an open-label trial reported by Antonio Ribas, MD, PhD, of the University of California, Los Angeles.4

The study of lambrolizumab, which recently was granted “breakthrough therapy” status by the FDA, involved 135 patients, of whom 38% responded overall and 52% responded to the dose of 10 mg/kg every 2 weeks. Median progression-free survival exceeded 7 months, and responses were durable in the majority of patients. At a median follow-up of 11 months, 81% of the responding patients were still on treatment.

“Importantly, we found that efficacy and safety were similar in ipilimumab (Yervoy)-naive patients and those who had received prior treatment with ipilimumab,” Dr. Ribas noted.

Clinical development of lambrolizumab is ongoing in melanoma, non–small cell lung cancer, breast cancer, head and neck cancer, and bladder cancer. A global phase II study of the drug vs chemotherapy for ipilimumab-refractory advanced melanoma patients will enroll 510 patients.

Two Supportive Care Interventions Ineffective

For patients being treated with FOLFOX (leucovorin, 5-FU, oxaliplatin) for colorectal cancer, intravenous calcium and magnesium did not reduce the risk of neuropathy associated with oxaliplatin. This study supports that this practice should be discontinued, said Charles
Loprinzi, MD
, of the Mayo Clinic, Rochester, Minnesota.5

The multicenter N08CB trial randomly assigned 350 patients receiving FOLFOX into three groups: one receiving the calcium/magnesium infusion before and after chemotherapy, a second receiving placebo, and a third receiving calcium/magnesium before chemotherapy and a placebo afterward.

Symptoms of neuropathy, which were measured in multiple ways, were no different among the groups, nor were there differences in the average number of days until symptoms became significant, or in the number of patients who discontinued chemotherapy. The study was called “practice changing,” by Richard H. Wilson, MD, of Queen’s University Belfast in Northern Ireland, who commented on the findings at a “Highlights of the Day” ASCO session, and supported immediate cessation of this intervention.

Another study called into question the clinical benefit of a common intervention in lung cancer. In a phase III study of 208 patients, modafinil given at a dose of 100 mg for 14 days followed by 200 mg for 14 days, did ameliorate fatigue, as determined by the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue subscale.6 At 28 days, patients receiving modafinil had a change of 5.38 points compared to 5.11 points among patients receiving placebo, and no dose-response relationship was observed, reported Kate Fife, MD, of the NIHR Cambridge Biomedical Research Centre in the United Kingdom.

“Thus, the improvement in fatigue score was the same in both arms of the study, showing that the placebo effect was at work and that placebo was equally effective as modafinil,” explained Dr. Fife.

The study discussant, Debra L. Barton, RN, PhD, of the Mayo Clinic, said the results call into question the clinical guidelines for treating fatigue in patients with cancer, which recommend that providers consider using psychostimulants to control fatigue, regardless of stage of disease or expectations for survival. “I think it is time to re-evaluate guidelines, and until there are more data to support psychostimulants, their use in clinical practice needs to be scrutinized,” Dr. Barton said.

Middle-aged Fitness Level Predicts Cancer Risk

Men with a high level of cardiovascular fitness in middle-age have a reduced risk of developing and dying from lung and colorectal cancer, as well as dying from prostate cancer, compared with their less fit counterparts according to a large prospective population-based study.7 As is well known, men with good cardiovascular fitness are also at lower risk of death due to cardiovascular causes.

Lead author Susan Lakoski, MD, of the University of Vermont, Burlington, explained that fitness level—as measured in this study—is an independent predictive marker distinct from body weight and/or exercise level.

“This is the first study to explore fitness as a marker of future cancer risk prognosis. This finding makes clear that patients should be advised that they need to achieve a certain level of fitness, and not just be told that they need to exercise. Unlike exercise behavior, fitness level can be measured objectively in a clinical setting. Previous studies have shown that poor fitness level is associated with increased risk of cardiovascular disease,” Dr. Lakowski stated.

The findings were based on the large, prospective Cooper Center Longitudinal Study, conducted at the Cooper Clinic in Dallas. The men (n = 17,049) had a single cardiovascular fitness assessment as part of a preventive health checkup at a mean age of 50 years. The fitness test involved treadmill-walking under conditions of changing speed and elevation, and performance was measured by units of fitness called metabolic equivalents (METs).

At a median follow-up of 20 to 25 years, 2,332 men were diagnosed with prostate cancer, 276 with colorectal cancer, and 277 with lung cancer, according to Medicare claims. Cancer deaths numbered 347, and 159 men died of cardiovascular disease.

In an adjusted analysis for smoking, body mass index, age, and other factors, men with the highest levels of fitness had a 68% lower risk of a diagnosis of lung cancer compared with men in the lowest fitness quintile; the risk of colorectal cancer was reduced by 38% in the highest vs the lowest quintile for fitness. No impact of fitness was found for development of prostate cancer.

Among those who developed cancer, men at the higher levels of fitness had a lower risk of cancer-related death from all three cancers, as well as a lower risk of death due to cardiovascular disease. Dr. Lakowski said that even a 1-MET different reduced the risk of dying from cancer and cardiovascular disease by 23% and 14%, respectively.

Low fitness levels were associated with increased risk of cancer and cardiovascular disease independently of body weight.

Black Women, Breast Cancer, and Genetic Mutations

About 1 in 5 African American women with breast cancer who were referred for genetic counseling were found to carry a mutation in at least 1 of 6 genes associated with increased risk of developing breast cancer.8 These damaging mutations were more prevalent in women with triple-negative breast cancer, early-onset breast cancer, and a family history of breast and ovarian cancer.

The majority of mutations found were in BRCA1 and BRCA2, but 21% of the mutations identified  with next-generation sequencing of 18 genes involved in breast cancer susceptibilty were in other genes that had clear associations with breast cancer susceptibility.

This was the first comprehensive screen of all known breast cancer susceptibility genes in black women, said lead author Jane E. Churpek, MD, of The University of Chicago. She said that the findings suggest that testing for BRCA1 and BRCA2 mutations alone may not be sufficient for black women.

The study population included 249 unrelated black women with breast cancer referred for genetic counseling at The University of Chicago. A single genomic test called the BROCA assay was used to screen for mutations in 42 genes, including 18 known breast cancer susceptibility genes. Of these women, 27 had a known BRCA1 or BRCA2 mutation.

Screening identified 58 clearly damaging inherited mutations in six different genes in 56 of the 249 women (22%). The breakdown of mutations identified is as follows: 79% in BRCA1 or BRCA2, and 21% in other genes that included ATM, CHEK2, PALB2, and PTEN.

Most of the women who had a mutation had only one, but three women—all with early-onset breast cancer—had more than one inherited mutation, and two of them had no family history of breast or ovarian cancer. Factors associated with an increasing number of mutations included younger age at diagnosis, a second diagnosis of breast or ovarian cancer, triple-negative breast cancer, a family history of breast, ovarian, or pancreatic cancer, and grade 3 breast cancer.

Dr. Churpek said that the majority of mutations found in these women were unique to an individual patient. By contrast, other populations such as Ashkenazi Jews carry one of three specific mutations in the BRCA1 and BRCA2 genes, thus allowing genetic testing to begin with these 3 specific genetic sites, rather than by sequencing the whole genes which is more expensive. Dr. Churpek pointed out that this study shows that such site-specific genetic testing is not adequate for black women, because they have such diverse inherited mutations.

A test like BROCA allows assessment of several types of genetic abnormalities including single nucleotide changes, small insertions and deletions, and large genomic rearrangements in multiple genes at the same time; previously, multiple tests were needed for this type of assessment, showing the potential for a more cost-effective and efficient approach to genetic testing. 

HPV-related Oropharyngeal Cancer in Patients’ Spouses

In a study that should be reassuring to those married or partnered with a patient with human papillomavirus (HPV)-positive oropharyngeal cancer, no increased risk of oral HPV infection was identified in spouses/partners of patients with HPV-positive oropharyngeal cancer.9 Most often HPV-positive oropharyngeal cancer occurs in males, and some spouses worry about their own HPV exposure and cancer risk, explained lead author ­Gypsyamber D’Souza, PhD, MPH, MSA, of Johns Hopkins University, Baltimore.

The Human Oral Papillomavirus Transmission in Partners over Time [HOTSPOT] is the first study to examine oral HPV prevalence among spouses of patients with HPV-positive oropharyngeal cancer. “The study suggests that long-term couples have already shared whatever infections they have, and no changes in their physical intimacy are required,” Dr. D’Souza said.

HOTSPOT enrolled 166 patients with HPV-positive oropharyngeal cancer and 94 spouses/long-term partners. Of the 166 patients, 147 were male and 19 were female. Median age was 56 years. An oral rinse/gargle sample was used to measure HPV DNA in spouses and partners.

Among the cancer cases, 65% of cases had HPV detected at diagnosis, and most cases no longer had HPV detectable after therapy. The overall prevalence of HPV infection among partners was 7.2%. The prevalence among the female partners was 5%, which is similar to women in the general population, she noted. HPV16, the subtype responsible for most cases of HPV-positive oropharyngeal cancer, was detected in 54% of patients but only 2.7% of the 88 female partners and none of the 6 male partners.

Five (3.4%) of the male cases reported having a partner who developed cervical cancer or precancer. A history of cervical cancer was reported in one current partner and two previous partners, and a history of cervical dysplasia was reported in two current partners of HPV-positive oropharyngeal cancer cases.

“It is not known how HPV is transmitted. The presumption is that oral sex is a route of transmission from the female genitals to the oropharynx, but there is no evidence that saliva transmits it to the genitals,” she said.

New Drugs for Acute Lymphocytic Leukemia

“We’ve reached the limits of what we can do for older adults with acute lymphocytic leukemia [ALL] using standard therapies. Progress will come from monoclonal antibodies and other novel therapies, and we have some encouraging data,” stated Mark Litzow, MD, of Mayo Clinic College of Medicine, Rochester, Minnesota, during an Education Session at the ASCO Annual Meeting.10

Novel monoclonal antibodies being studied in adults with ALL include epratuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, and blinatumomab. Also, preliminary studies using a patient’s own genetically engineered T cells are encouraging thus far.

Epratuzumab is a humanized antibody that binds to the CD22 antigen expressed on B-lineage ALL cells. Small studies show that this drug in combination with chemotherapy has good activity in ALL.

Gemtuzumab ozogamicin is a mono­clonal antibody directed against the CD33 antigen expressed on leukemic cells and was primarily used in acute myeloid leukemia. This drug is no longer on the U.S. market, but the mechanism of action is attractive, which led to the development of inotuzumab ozogamicin, Dr. Litzow said.

Preliminary study of inotuzumab showed impressive results in relapsed/refractory ALL, allowing approximately one-third of 89 patients to go on to stem cell transplantation, but like gemtuzumab, the drug can be associated with hepatic toxicity.

A novel anti-CD22 murine monoclonal antibody called moxetumomab pasudotox is being studied in ALL, but these studies are still accruing patients, and, although it improves response, results are preliminary, Dr. Litzow said.

Blinatumomab, a bi-specific T-cell engaging (BiTE) antibody directed against CD19, shows good activity in patients with B-precursor ALL with minimal residual disease. Of 20 evaluable patients receiving blinatumomab, 16 achieved minimal residual disease negativity. The drug is now being tested in a clinical trial in relapsed/refractory patients. Safety concerns include cytokine release syndrome and central nervous system adverse events. This drug could be considered as a bridge to transplantation and can also be used in patients with prior transplant. There are plans to study blinatumomab in a randomized trial of patients with ­newly diagnosed Philadelphia-negative B‑cell ALL starting later this year.

Chimeric antigen receptor–modified (CAR) T cells offer an intriguing immunologic therapy under study in ALL as well as in other leukemias, Dr. Litzow continued. Reports have been published in small groups of patients treated with CAR-T, including five pediatric patients with ALL and five adults with refractory ALL or minimal residual disease. A few end-stage patients have had life-saving results with this therapy, which have been reported in The New York Times and other newspapers.

“This therapy may enable patients to avoid transplantation, but the jury is still out,” he said. “We are going to hear much more about this form of therapy as time goes on.”

Lung Cancer Stigmatized Compared with Breast Cancer

Patients with cancer, physicians, other health-care specialists, and caregivers have negative attitudes toward lung cancer, whereas this is not true for breast cancer, according to a study that quantitated and characterized attitudes toward both types of cancer.11

In this online study, 1,778 participants responded to a set of exercises specifically designed to elicit explicit and implicit attitudes toward lung and breast cancer. A 6-point scale to measure explicit attitudes revealed significantly more negativity toward lung cancer than breast cancer (P < .001). Implicit attitudes were also significantly more negative toward lung cancer than breast cancer (P < .0001). For both explicit and implicit attitudes, females had much stronger negative attitudes than males.

More research is needed to determine whether these attitudes affect care, said lead author Joan Schiller, MD, of the University of Texas Southwestern, Dallas.

Dr. Schiller noted that lung cancer is perceived as self-induced due to its strong association with smoking cigarettes, but that addiction to tobacco is powerful and very difficult to break. The stigmatization of lung cancer leaves these patients without powerful advocacy groups for support, and this extends to patients with lung cancer who never smoked cigarettes. By contrast, many advocacy groups and support groups are available for patients with breast cancer. ■

Disclosure: Dr. O’Regan has served as a consultant or advisor for Novartis and has received research funding from Genentech and Novartis. Dr. Hecht has received research funding from GlaxoSmithKline. Dr. Palumbo has served as a consultant or advisor for and has received honoraria from Celgene. Dr. Lonial has been a consultant for Millennium, Celgene, Novartis, Bristol-Myers Squibb, and Onyx. Dr. Ribas has served as a consultant or advisor for Amgen, Genentech, GlaxoSmithKline, Merck, and Novartis, and owns stock in Kite Pharma. Dr. Wilson has served as a consultant or advisor for Merck Serono, Pfizer, Roche/Genentech, and Sanofi, and has received honoraria from Hospira. Dr. D’Souza has received research funding from Merck. Dr. Schiller has served as a consultant or advisor for Genentech. Dr. Litzow has served as a consultant or advisor for Talon Therapeutics, has received honoraria from Amgen and Sigma-Tau, and has received research funding from Amgen. Drs. Loprinzi, Fife, Barton, Lakoski, and Churpek reported no potential conflicts of interest.

References

1. O’Regan R, Ozguroglu M, Andre F, et al: Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3). 2013 ASCO Annual Meeting. Abstract 505. Presented June 2, 2013.

2. Hecht JR, Bang Y-J, Qin S, et al: Lapatinib in combination with capecitabine plus oxaliplatin in HER2-positive advanced or metastatic gastric, esophageal or gastroesophageal adenocarcinoma: The TRIO-013/LOGiC trial. 2013 ASCO Annual Meeting. Abstract LBA4001. Presented June 3, 2013.

3. Boccadoro M, Cavallo F, Gay FM, et al: Melphalan/prednisone/lenalidomide versus high-dose melphalan and autologous transplantation plus lenalidomide maintenance or not maintenance in newly diagnosed multiple myeloma patients. 2013 ASCO Annual Meeting. Abstract 8509. Presented June 3, 2013.

4. Ribas A, Robert C, Daud A, et al: Clinical efficacy and safety of lambrolizumab (MK-3475, anti-PD-1 monoclonal antibody) in patients with advanced melanoma. 2013 ASCO Annual Meeting. Abstract 9009. Presented June 1, 2013.

5. Loprinzi CL, Qin R, Dakhil SR, et al: Phase III randomized, placebo-controlled, double-blind study of intravenous calcium/magnesium to prevent oxaliplatin-induced sensory neurotoxicity, N08CB: An alliance for clinical trials in oncology. 2013 ASCO Annual Meeting. Abstract 3501. Presented June 1, 2013.

6. Fife K, Spathis A, Dutton SJ, et al: A multicenter, randomized, double-blinded, placebo-controlled trial of modafinil for lung cancer-related fatigue. 2013 ASCO Annual Meeting. Abstract 9503. Presented June 2, 2013.

7. Lakoski SG, Barlow C, Gao A,, et al: Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study. 2013 ASCO Annual Meeting. Abstract 1520. Presented June 2, 2013.

8. Churpek JE, Walsh T, Zheng Y, et al: Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next generation sequencing. 2013 ASCO Annual Meeting. Abstract CRA1501. Presented June 3, 2013.

9. D’Souza G, Gross ND, Pai SI, et al: Oral HPV infection in HPV-positive oropharyngeal cancer cases and their spouses. 2013 ASCO Annual Meeting. Abstract CRA6031. Presented June 1, 2013.

10. Litzow MR: Monoclonal antibody-based therapies in the treatment of acute lymphoblastic leukemia (ALL). 2013 ASCO Annual Meeting. Education Session. Presented May 31, 2013.

11. Schiller JH, Bowden CJ, Mills J, et al: Explicit and implicit attitudes toward lung cancer, relative to breast cancer. 2013 ASCO Annual Meeting. Abstract 8017. Presented June 3, 2013.



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