You are here
American Society of Clinical Oncology 2016
More than 35,000 cancer professionals attended this premier annual oncology meeting in Chicago, Illinois, June 3–7. We review key sessions across a wide range of disease states, including breast cancer, multiple myeloma, pancreatic cancer, glioblastoma, ovarian cancer, and melanoma.
A Randomized Trial of Extending Adjuvant Letrozole for Five Years After Completing an Initial Five Years of Aromatase Inhibitor Therapy Alone Or Preceded by Tamoxifen In Postmenopausal Women With Early-Stage Breast Cancer
Prior research by Dr. Goss showed that five years of letrozole extended disease-free survival by 43% (P ≤ 0.001) and overall survival by 24% (P = 0.25) versus placebo in women with early-stage hormone receptor-positive breast cancer. This population, however, faces an indefinite risk of relapse. The phase 3 MA.17R trial was designed to elucidate the value of continued aromatase inhibitor therapy in preventing recurrences. In it, investigators extended adjuvant letrozole (2.5 mg orally once daily) or placebo for five years after an initial 4.5 to six years of aromatase inhibitor therapy alone or preceded by tamoxifen. The trial included 1,918 postmenopausal women with early-stage breast cancer.
After a median follow-up of 6.3 years, a 34% reduction in recurrence risk was found for letrozole compared with placebo (hazard ratio [HR], 0.66; P = 0.01). A 58% reduction in occurrence of contralateral breast cancer in women receiving extended letrozole was also significant (HR, 0.42; P = 0.007). Overall survival was similar between groups, however (HR for letrozole, 0.97; P = n.s.).
Osteoporosis was doubled in the letrozole group, with more bone fractures (133 letrozole, 88 placebo). No emergent symptoms or toxicities were observed, however. While there was no worsening of quality of life in either group, physical function was better in the placebo group. The difference, Dr. Goss said, was less than clinically meaningful. He acknowledged, however, “Bone health remains as an important factor in risk–benefit considerations.”
“Ten years of any therapy is a long time,” commented ASCO breast cancer expert Harold J. Burstein, MD. “Fortunately, most women tolerate extended treatment reasonably well, with few side effects,” he added. “Now, women can talk with their clinical team and make informed decisions to extend adjuvant endocrine therapy or not.”
Dr. Goss concluded, “Unlike many anticancer therapies, aromatase inhibitors are readily accessible around the world, and, therefore, our results will further improve the outcome for many women with breast cancer.”
The study was published online in the New England Journal of Medicine concurrently with presentation on June 5, 2016.1
Lenalidomide Maintenance After High-Dose Melphalan and Autologous Stem Cell Transplant In Multiple Myeloma: A Meta-Analysis of Overall Survival
Most autologous stem cell transplant (ASCT) patients with multiple myeloma will relapse or progress, Dr. McCarthy said— even those who have a complete response. While lenalidomide maintenance has been shown to reduce the risk of progression or death by about 50%, past studies have used progression-free survival (PFS) as their endpoint and have not examined overall survival (OS). To elucidate the OS of lenalidomide maintenance, Dr. McCarthy conducted a meta-analysis of three multiple myeloma trials (CALGB 100104, IFM 2005-02, and GIMEMA [RV-MM-PI-209]), which included 605 patients treated with lenalidomide and 604 with placebo or no treatment. All patients had been randomized after ASCT to lenalidomide or control until progression. Lenalidomide maintenance in the IFM 2005-02 study was discontinued after a signal for increased rates of secondary primary malignancies (SPMs) was detected.
Seven-year OS in the pooled studies after a median follow-up of 80 months was 62% in the lenalidomide maintenance arm and 50% in controls (hazard ratio [HR], 0.74; 95% confidence interval, 0.62–0.89; P = 0.001). HRs favored lenalidomide for each of the trials considered separately (CALGB HR, 0.56; IFM HR, 0.91; and GIMEMA HR, 0.66). The findings show, Dr. McCarthy said, that lenalidomide maintenance is feasible for long-term disease control after ASCT.
Subgroup analysis showed an OS benefit for lenalidomide maintenance regardless of age, gender, or response after ASCT, but with greater benefit among those with stronger post-ASCT responses.
For both hematological (HR, 2.03; P = 0.15) and solid tumors (HR, 1.71; P = 0.032), cumulative incidence of SPMs was significantly higher in the lenalidomide maintenance groups. Putting that finding in a risk–benefit context, Dr. McCarthy commented, “There was a 26% reduction in the risk of death, representing an estimated 2.5-year increase in median survival. So the overall survival benefit of lenalidomide maintenance outweighs the risk of developing an SPM.”
Speaking further about SPM risk, Markus Renschler, MD, Global Head for Hematology and Oncology Medial Affairs at Celgene, the manufacturer of lenalidomide, said, “While the absolute risk for a secondary primary malignancy was nearly doubled, the actual risk is very low. The 26% improvement in overall survival includes that risk.” Dr. Renschler pointed out further in an interview that in the IFM study (the study in which lenalidomide maintenance was discontinued following the detection of SPM increase), the median survival duration was five months shorter than in the other trials that had continued lenalidomide treatment.
Dr. McCarthy concluded, “Lenalidomide maintenance after ASCT can be considered a standard of care.”
HERITAGE: A Phase 3 Safety and Efficacy Trial of the Proposed Trastuzumab Biosimilar MYL-1401O Versus Herceptin
While biologics are complex proteins with high molecular weight, traditional small-molecule agents are usually simple chemicals with relatively low molecular weight. They are highly targeted. Trastuzumab, for example, has revolutionized the treatment of human epidermal growth factor receptor-2-positive (HER2+) breast cancer. Because these biologics are costly, however, access across the globe is limited, Dr. Rugo said. “Many biologics are losing patent protection soon; biosimilars have the potential to significantly improve access to expensive agents.” To achieve regulatory approval, however, they must demonstrate high structural and functional similarity to the reference drug. To date, no biosimilars for the treatment of cancer have been approved in the U.S. or Europe, although the Food and Drug Administration approved one biosimilar supportive drug last year.
Dr. Rugo conducted the HERITAGE study comparing a biosimilar, MYL-1401O, to its reference product, Herceptin (trastuzumab, Genentech), in 500 women with metastatic HER2+ breast cancer. The randomized, double-blind, phase 3 trial was conducted at 95 sites across Asia, Latin America, Africa, and Europe. All participants received taxane chemotherapy with either trastuzumab or MYL-1401O. The primary endpoint of objective response rate at 24 weeks was reported at 69.6% with MYL-1401O and at 64% with trastuzumab. The lack of difference was within a predetermined equivalence margin.
Trastuzumab’s published data show low immunogenic potential. Importantly, immunogenicity was similarly low for the biosimilar agent. Overall the drug antibody rates for MYL-1401O and for trastuzumab were 2.4% and 2.8%, respectively. Rates of serious side effects were also similar at 36% in the trastuzumab group and 38% in the MYL-1401O group.
“This was one of the first trials with biosimilars in oncology to demonstrate such equivalence,” Dr. Rugo said. “MYL-1401O has the potential to meet the need for an affordable treatment option for patients with HER2+ cancers.”
Findings From a Phase 3 Trial Comparing Adjuvant Gemcitabine and Capecitabine Chemotherapy to Gemcitabine Alone Following Pancreatic Cancer Surgery
Pancreatic cancer is the third most common cause of cancer death in the U.S. For the small proportion of pancreatic cancer patients who are candidates for surgery, adjuvant gemcitabine chemotherapy is the standard of care worldwide. “We thought that the combination of gemcitabine plus capecitabine might be better than gemcitabine alone,” Dr. Neoptolemos said at an ASCO press conference.
In the ESPAC 4 trial, researchers at 92 European sites randomized patients with resected pancreatic ductal adenocarcinoma to gemcitabine (n = 361) or gemcitabine and capecitabine (n = 361) within 12 weeks of surgery. The primary endpoint was overall survival (OS). Dr. Neoptolemos said that a large proportion of the patients had unfavorable prognostic factors, such as locally advanced or aggressive disease, large tumor size, or incomplete tumor resection. The included population, he added, was representative of a real-world pancreatic cancer population.
Median OS of 28.0 months with the combination regimen compared favorably to 25.5 months for gemcitabine alone. Estimated five-year survival increased with the combination at 28.8%, compared with 16.3% for gemcitabine alone. “The difference in median survival may seem modest,” Dr. Neoptolemos said, “but the improvement in long-term survival is substantial for this cancer.” Five-year survival with surgery alone, he said, is about 8%.
Serious adverse event rates were similar between groups at 26% for gemcitabine alone and 24% for the combination. In general, toxicities were manageable and acceptable.
The combination, he said, is a new standard of care. “These findings are significant because they show that those patients who can undergo surgery have a fighting chance of surviving this cancer with the combination of two commonly used chemotherapies.”
ASCO pancreatic cancer expert Smitha Krishnamurthi, MD, commented, “Pancreatic cancer remains one of the most hard-to-treat cancers. It is a major win to find that adding a generic chemotherapy not only improves survival for these patients, but does so with little effect on patients’ quality of life.”
A Phase III Randomized Controlled Trial of Short-Course Radiotherapy With or Without Concomitant and Adjuvant Temozolomide in Elderly Patients With Glioblastoma
Glioblastoma affects older patients disproportionately. Prior research has shown that, in elderly patients with glioblastoma, the best practice is surgical resection with six weeks of radiation combined with chemotherapy (oral temozolomide), according to Dr. Perry. Inclusion criteria in this pivotal trial, however, allowed only patients younger than 70 years of age, and few patients older than 65 years of age were included. Trials in the elderly, Dr. Perry said in an ASCO press conference, have compared different radiation schedules or compared radiation to temozolomide, but have not tested combined therapy. Clear treatment guidelines are lacking and practices vary globally.
The Canadian Cancer Trials Group international phase 3 trial was the first study to test temozolomide chemotherapy during short-course radiation therapy followed by monthly maintenance temozolomide doses in elderly patients with glioblastoma. Investigators enrolled 562 newly diagnosed patients age 65 years and older and assigned them randomly 1:1 to short-course radiation therapy (40 Gy in 15 fractions over three weeks) with or without concurrent and adjuvant temozolomide (12 cycles). The primary endpoints were progression-free survival (PFS), overall survival (OS), and quality of life.
Dr. Perry reported that the temozolomide/radiation combination conferred longer median survival (9.3 months versus 7.6 months [hazard ratio, 0.67; 95% confidence interval, 0.56–0.80; P < 0.0001]). Median PFS was longer for the combination at 5.3 months versus 3.9 months for radiation alone. The one-year and two-year survival rates were 37.8% and 10.4% with radiation therapy plus temozolomide compared with 22.2% and 2.8% with radiation therapy alone. Dr. Perry emphasized that the improvements, while modest, are meaningful.
Median OS is generally longer among glioblastoma patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and that was the case among 165 patients in this trial with the MGMT genetic abnormality (13.5 months with temozolomide/radiation versus 7.7 months with radiation alone). Dr. Perry underscored that some patients with unmethylated tumors did derive clinical benefit from adding temozolomide to radiation therapy.
An expected slight increase in grade-3 and -4 hematological toxicity was reported in the combination group. Also, nausea, vomiting, and constipation were more common among those receiving temozolomide.
“Patients were, however, able to easily complete the treatment plan,” Dr. Perry said. Adherence to the three weeks of chemoradiation was more than 97%. Standardized quality-of-life measures (the European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire–Core 30 and the EORTC Quality of Life Questionnaire–Brain Neoplasm) showed no differences in physical, cognitive, emotional, and social functioning between groups.
“Oncologists now have evidence to consider radiation therapy with temozolomide in all newly diagnosed elderly patients with glioblastoma,” Dr. Perry said.
OV21/PETROC: A Randomized Gynecologic Cancer Intergroup (GCIG) Phase II Study of Intraperitoneal Versus Intravenous Chemotherapy Following Neoadjuvant Chemotherapy and Optimal Debulking Surgery in Epithelial Ovarian Cancer
Epithelial ovarian cancer, the fifth most common cancer in women, usually presents at advanced stages (stage III/IV) with high mortality rates. In the United States, about 40% of women with epithelial ovarian cancer receive neoadjuvant chemotherapy. While sparing other parts of the body from potentially toxic doses, intraperitoneal (IP) chemotherapy allows the delivery of higher doses of chemotherapy to the tumor, Dr. Mackay said at an ASCO press conference. The OV21/PETROC study evaluated whether patients receiving neoadjuvant chemotherapy followed by optimal cytoreductive surgery benefit from IP chemotherapy with carboplatin and paclitaxel.
Dr. Mackay’s study included 200 women with epithelial ovarian cancer who were randomly assigned to intravenous (IV) chemotherapy with or without IP chemotherapy after they had undergone debulking surgery.
Nine months after treatment, the disease progression rate was 18.9 percentage points lower among women receiving IP chemotherapy (per protocol, 42.2%; 95% confidence interval [CI], 31.9–53.1; chemotherapy, 23.3%; 95% CI, 15.1–33.4; IP/chemotherapy, P = 0.01). While median overall survival was longer in the IP/chemotherapy group (38.1 months versus 59.3 months; hazard ratio, 0.80; 95% CI, 0.47–1.35), the difference was not statistically significant (P = 0.40). Dr. Mackay noted that the trial was not powered to detect an overall survival difference.
No differences between groups were detected in a quality-of-life analysis. “At this early time frame,” Dr. Mackay said, “we already see that women are doing better with IP/chemotherapy, without a significant difference in toxicity.”
Dr. Mackay noted that this was the first randomized study to explore the benefit of IP chemotherapy plus IV chemotherapy in women with epithelial ovarian cancer.
“This study provides reassurance for patients and providers,” said Don Dizon, MD, the press conference moderator, “that the carboplatin-based IP regimen is both effective and well tolerated with maintenance of quality of life. That said, we need to further define those who derive the greatest benefit from this approach and to identify better options for all women with ovarian cancer.”
Preliminary Results From Phase 2 Study of Combination Treatment With HF10, a Replication-Competent HSV-1 Oncolytic Virus, and Ipilimumab In Patients With Stage IIIb, IIIc, or IV Unresectable Or Metastatic Melanoma
HF10 is a spontaneously occurring mutant (not genetically modified) of the HF strain of herpes simplex virus type 1 (HSV-1). When combined as an intralesional therapy with systemic ipilimumab, it has both local and systemic activity in patients with metastatic malignant melanoma, according to Dr. Andtbacka’s phase 2 study.
The study enrolled 46 patients (median age, 67 years; 59% male) with stage IIIb, IIIc, or IV unresectable/unresected metastatic malignant melanoma who were given intratumoral injections of HF10 at 1x107 TCID50/mL in combination with intravenous infusions of 3 mg/kg ipilimumab. Sixty-five percent were HSV-1 antibody positive. For this analysis, the primary endpoint was best overall response at 24 weeks.
Maximal changes in tumor burden were as follows: complete response (CR) in 12%, partial response (PR) in 28%, stable disease (SD) in 25%, clinical benefit (CR+PR+SD) in 65%, and progressive disease in 30%. Overall response (CR+PR) was 40%. “This is very encouraging,” Dr. Andtbacka said in an interview.
A post-24-week analysis revealed a trend toward increasing responses with a CR of 14% and PR of 35% (49% overall response). Responses were observed in 53% (eight) of the stage IV patients. The fact that about half of the patients had prior therapy made these findings especially impressive, Dr. Andtbacka said.
Grade 3 and higher toxicities were generally related to ipilimumab. While all patients experienced some treatment-emergent adverse events, grade 3 or higher events related to HF10 were reported in only four patients (9%), and none discontinued treatment because of them. Adverse events were consistent with those reported for other oncolytic viruses (grade 2 or lower chills, fatigue, headache, injection site reaction, malaise, nausea, and pruritus).
“Preliminary efficacy evaluation suggests HF10 plus ipilimumab has both local and systemic antitumor activity and substantially improves the response rate of ipilimumab alone and does not exacerbate ipilimumab toxicity,” Dr. Andtbacka concluded.
Dr. Antbacka also commented on a further phase 2 trial of a different intralesional therapy, the chemo-ablative agent PV-10 combined with radiotherapy. Conducted among metastatic melanoma patients who failed to achieve a CR with PV-10, the study led by Matthew C. Foote, MD, of Princess Alexandra Hospital and University of Queensland in Brisbane, Australia, included 13 patients (mean age, 69 years). Commencing six to 10 weeks after injections of PV-10, they were treated with 30 Gy (six fractions of 5 Gy twice weekly over three weeks) 3-D conformal radiotherapy (photons or electrons).
The overall response rate after a median follow-up of 19.3 months was 87% (CR, 33%; PR, 53%), with a 12.2-month mean duration of CRs. CRs were more likely with metastases smaller than 10 mm. Treatment was well tolerated.
Dr. Andtbacka commented, “We see that adding radiation, in this small series, led to improved responses. The finding suggests larger studies combining PV-10 with radiation in patients who are not fully responding. ”
Finally, Dr. Andtbacka commented on intralesional therapy with a second oncolytic virus, coxsackievirus A21 (CVA21). He noted that in patients for whom treatment with ipilimumab, pembrolizumab, or nivolumab had failed, biopsies showed very few tumor-infiltrating lymphocytes (TILS). In these patients, however, after only three injections of CVA21 there was a very robust increase in TILS including CD8+ T cells. “So that raises the question, ‘Can we now add back the checkpoint inhibitor and get a response?’ We’re now studying that,” he said.
- Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 2016 Jun 5. [Epub ahead of print]. Available at: www.nejm.org/doi/full/10.1056/NEJMoa1604700#t=article.