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American Society of Clinical Oncology 2015
The American Society of Clinical Oncology (ASCO) 2015 Annual Meeting, held from May 29 to June 2 in Chicago, Illinois, hosted approximately 30,000 medical professionals, about half of them international attendees. We review key research findings in therapies for renal cell carcinoma, prostate cancer, melanoma, myelofibrosis, multiple myeloma, and chronic lymphocytic leukemia.
RECORD-4: A Multicenter, Phase II Trial of Second-Line Everolimus in Patients With Metastatic Renal Cell Carcinoma
The RECORD-1 trial showed everolimus to be superior to placebo in patients with metastatic renal cell carcinoma (mRCC) who had been treated previously with sunitinib, sorafenib, or both or with cytokines, bevacizumab, and other chemotherapy. RECORD-4 results reinforced those findings for everolimus in second-line treatment of mRCC.
In RECORD-1, median progression-free survival (PFS) was 4.9 months with everolimus and 1.9 months with placebo (hazard ratio [HR], 0.33; P < 0.001). Subanalysis showed longer median PFS in patients who had received one vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFR-TKI) than for those who had received two VEGFR-TKIs (5.4 months versus 4.0 months).
RECORD-4 prospectively assessed pure second-line treatment of mRCC with everolimus among patients who had progressed after first-line treatment with an anti-VEGF or cytokine agent. Patients (n = 134) received everolimus 10 mg per day until progressive disease or intolerance. Tumor evaluations were conducted every eight weeks until documented progressive disease or initiation of third-line therapy. The primary endpoint of the open-label, multicenter, international phase 2 study was PFS.
Fifty-eight patients had received first-line sunitinib and 62 had received other first-line anti-VEGF agents (bevacizumab, pazopanib, tivozanib, axitinib). Dr. Motzer reported that PFS was 7.8 months (95% confidence interval [CI], 5.7–11.0). Analysis by first-line treatment revealed PFS of 5.7 months in those who had received first-line sunitinib (n = 58), 7.8 months with other first-line VEGF therapy (n = 62), and 12.9 months with first-line cytokine therapy (n = 14).
Most patients achieved stable disease (first-line sunitinib, 64%; other anti-VEGF therapy, 73%; first-line cytokine therapy, 57%). Partial responses were achieved in 7% of patients with prior sunitinib as first-line treatment, 5% with other anti-VEGF therapy, and 21% with first-line cytokine-based therapy.
Consistent with RECORD-1, rates of grade 3–4 adverse events (AEs) were 55%, 52%, and 71% for prior sunitinib, other anti-VEGF therapies, and cytokine-based therapies, respectively. Thirteen on-treatment deaths occurred.
“RECORD-4 results confirm the progression-free survival benefit with everolimus in a second-line setting,” Dr. Motzer concluded. ASCO discussant Bernard Escudier, MD, of Gustave Roussy in Villejuif, France, agreed: “Progression-free survival observed in RECORD-4 confirms the efficacy of everolimus in the second-line setting.”
A Phase III Protocol of Androgen Suppression And 3DCRT/IMRT Versus AS and 3DCRT/IMRT Followed by Chemotherapy With Docetaxel and Prednisone for Localized, High-Risk Prostate Cancer (RTOG 0521)
For the first time, improvements in overall survival (OS) were reported in localized, high-risk, hormone-sensitive prostate cancer with a tolerable adjuvant chemotherapy regimen, Dr. Sandler said. Generally, the prognosis for this population is relatively poor.
Standard management often includes radiation and long-term hormonal treatment (two to three years). Dr. Sandler hypothesized that adding chemotherapy to radiation therapy would be beneficial for patients with nonmetastatic hormone-sensitive prostate cancer. Docetaxel chemotherapy had already been shown to be beneficial in metastatic hormone-resistant prostate cancer.
Patients were assigned to one of two arms: the first receiving androgen suppression for 24 months and external radiotherapy (75.6 Gy) for eight weeks, and the second receiving the same therapy plus six cycles of docetaxel (75 mg/m2 on day 1 of six 21-day cycles plus prednisone 10 mg daily) beginning four weeks after radiotherapy. The primary endpoint was OS.
About half of the 563 evaluable patients had Gleason scores of 9–10, with prostate-specific antigen of 150 or less and any tumor stage. Patients’ median age was 66 years. “This was a subset of very high-risk prostate cancer patients,” Dr. Sandler said.
Four-year OS was 89% without docetaxel and 93% with docetaxel (HR, 0.79; 90% CI, 0.51–0.98, P = 0.04) after a median follow-up of six years. Distant metastases were detected in 26 patients receiving docetaxel and in 41 patients in the arm without docetaxel (P = 0.05). Blinded central review reported 16 cancer-related deaths in the docetaxel arm and 23 in the arm without docetaxel. The docetaxel arm had higher rates of grade 3–5 events that were deemed definitely, probably, or possibly related to treatment (65% versus 22%).
“I believe these results are clinically relevant,” said press conference moderator Don S. Dizon, MD, of Massachusetts General Hospital in Boston, “with wide implications, especially for those diagnosed with high-risk, locally advanced prostate cancer.”
Dr. Sandler noted that the findings were consistent with those reported for the STAMPEDE and CHAARTED trials. “Longer-term follow-up will likely be enlightening,” he added.
Efficacy and Safety Results From a Phase III Trial of Nivolumab Alone or Combined With Ipilimumab Versus Ipilimumab Alone in Treatment-Naive Patients With Advanced Melanoma (CheckMate 067)
Results of the phase 3 CheckMate 067 trial showed strong efficacy with manageable toxicity for the combination of nivolumab and ipilimumab in advanced melanoma. PFS was numerically longer and the overall response rate (ORR) was significantly higher for the combination than for ipilimumab alone. The incidence of AEs, while higher for the combination, was consistent with earlier experience, Dr. Wolchok said at an ASCO press briefing.
The checkpoint inhibitors represent two distinct and complementary pathways that negatively regulate tumor immunity. Ipilimumab as monotherapy improves OS in melanoma, with about 20% of patients alive after three or more years. Phase 2 studies of nivolumab monotherapy have demonstrated one-year survival rates of 73% and ORRs of 40% in untreated melanoma (BRAF wild-type). In patients who had progressed after treatment with ipilimumab (or ipilimumab plus a BRAF inhibitor in BRAF mutation-positive patients), the ORR with nivolumab was 32%. Furthermore, in a phase 2 study of nivolumab plus ipilimumab in untreated melanoma, the ORR was high at 59% (11% for ipilimumab alone) and the complete response rate was 22%. Programmed death ligand 1 (PD-L1) expression did not affect response rates.
CheckMate 067, conducted at 137 sites globally, is the first phase 3 evaluation of the combination. It included 945 treatment-naïve patients with unresectable stage III or IV melanoma. They were randomized 1:1:1 to nivolumab 1 mg/kg every two weeks plus ipilimumab 3 mg/kg every three weeks for four doses followed by nivolumab 3 mg/kg every two weeks; nivolumab 3 mg/kg every two weeks plus placebo; or ipilimumab 3 mg/kg every three weeks for four doses plus placebo, until progression or unacceptable toxicity. The coprimary endpoints were PFS and OS (data not yet mature).
Patients’ median age was 61 years; approximately 65% were male. PD-L1 expression was 5% or greater in approximately 24% of patients. PFS in the intent-to-treat population was 11.5 months for the combination, 6.9 months for nivolumab alone, and 2.9 months for ipilimumab alone. The HR for nivolumab/ipilimumab versus ipilimumab was 0.42 (P < 0.00001) and for nivolumab alone versus ipilimumab was 0.57 (P < 0.00001). ORRs were 57.6% for the combination (P < 0.001 versus ipilimumab), 43.7% for nivolumab alone (P < 0.001 versus ipilimumab), and 19.0% for ipilimumab alone. PFS was longer and ORR was higher in patients with 5% or higher PD-L1 expression.
Dr. Wolchok emphasized that 67.5% of patients who discontinued nivolumab/ipilimumab treatment for treatment-related AEs still developed a response. Grade 3–4 treatment-related AEs were more common for the combination arm (55.0% versus 16.3% for nivolumab alone and 27.3% for ipilimumab alone). “We saw no drug-related deaths in the combination arm,” Dr. Wolchok said.
“Certainly this is a powerful combination, and toxicity is manageable in a global setting,” commented ASCO press briefing moderator Jyoti Patel, MD, of the Northwestern University Feinberg School of Medicine in Chicago.
PERSIST-1: Greater Spleen Volume Reduction With Pacritinib in Myelofibrosis
In patients with myelofibrosis, the incidence of disease-related thrombocytopenia, anemia, and the need for red blood cell transfusions increases dramatically within a year of diagnosis. While OS is likely to be shorter and leukemic transformation risks are higher with thrombocytopenia, current treatments have not been shown to simultaneously address splenomegaly, symptoms, and cytopenias in myelofibrosis populations.
Pacritinib, a potent JAK2 inhibitor, was evaluated versus best available therapy in patients with myelofibrosis in the phase 3 PERSIST-1 study. The study included 321 patients with either primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. The primary endpoint was the proportion of patients achieving at least a 35% spleen-volume reduction at week 24 by centrally reviewed magnetic resonance imaging or computed tomography. In a 2:1 randomization stratified for risk and platelet count, 220 patients received daily oral pacritinib and 107 received best available therapy. Best available therapy was “watch and wait” in 25.5% of cases, hydroxycarbamide in 55.7%, and small percentages (0.9%–6.6%) of 17 other agents in the remainder. Mean age was approximately 66 years, and approximately 57% were male.
Among patients receiving pacritinib, 19.1% achieved spleen-volume reduction of 35% or greater. The rate was 4.7% in patients receiving best available therapy (P = 0.0003) in an intent-to-treat analysis. Among evaluable patients, 25.0% of pacritinib patients and 5.9% of best-available-therapy patients had 35% or greater spleen-volume reductions (P = 0.0001), Dr. Mesa said. In both evaluations, spleen-volume reduction at this level was achieved among greater percentages of patients who had higher-risk disease with baseline thrombocytopenia platelet counts of less than 50,000/mcL versus those with less than 100,000/mcL. Changes from baseline were significant in all pacritinib groups.
Spleen-volume reductions correlated positively with OS in the pacritinib group achieving greater than 20% reductions (P = 0.014) but not among those receiving best available therapy in a landmark analysis at week 24. At this time, 50% or greater reductions in total symptom scores were found in 24.5% of patients in the pacritinib group compared with 6.5% in the best-available-therapy group (P < 0.0001). The benefit was greatest among patients with platelet counts greater than 100,000/mcL at baseline (24.3% versus 5.5%; P = 0.0004). In the evaluable group, the pattern was accentuated. While no patients in the best-available-therapy group achieved independence from red blood cell transfusions, a quarter of patients in the pacritinib group achieved independence (P = 0.043).
Dose reductions for AEs were necessary in 10% of patients receiving pacritinib. Dr. Mesa noted that benefits persisted irrespective of gastrointestinal side effects, most of which occurred in the first two weeks of treatment.
Dr. Mesa concluded, “Based on preliminary data, pacritinib may be disease modifying and warrants combination studies with other potentially disease-modifying agents in myeloproliferative neoplasms.”
Impact of Novel Therapies on Multiple Myeloma Survival in the US: Current and Future Outcomes
An estimate of the impact of new and emerging therapies for multiple myeloma found that patients’ life expectancy has risen dramatically but is still projected to remain a decade lower than that of the general population.
The immunomodulatory drugs and proteasome inhibitors (i.e., lenalidomide and bortezomib) introduced in the middle to late 2000s, Dr. Drawid said, “essentially transformed multiple myeloma from an acute condition to a potentially manageable chronic disease.” Based on multiple myeloma data from the Surveillance, Epidemiology, and End Results (SEER) Program, he derived historical perspective on OS in patients diagnosed in specific years and performed a predictive analysis of OS using a patient flow model simulating progression from clinical trials, cancer registries, demographics, and input from key opinion leaders.
While revealing relatively constant OS rates from 1973 to 2001, the historical review showed a slow rise with the introduction of stem-cell transplantation and thalidomide to about 20%–30%. OS then rose to nearly 45% in 2008, a 43% increase, after the introduction of novel treatments such as lenalidomide and bortezomib. The projections took into account likely benefits from second-generation protease inhibitors and immunomodulatory agents (carfilzomib and pomalidomide), and, further into the future, monoclonal antibodies and triplet therapies including ixazomib, elotuzumab, daratumumab, panobinostat, and SAR650984. His predictive analysis projected that median OS will increase to 72 months by 2022, representing about a 67% improvement from 2008 and about a 140% improvement from 2001.
According to Dr. Drawid’s projections, the life expectancy of a person diagnosed with multiple myeloma in 2022 would be about 75 years—still about a decade shorter than the roughly 86-year life expectancy in the general population at the median diagnosis age of 69 years.
The later adoption of novel therapies in Europe will likely produce a slight delay but similar survival trends. “Additional innovative therapies,” he observed, “are required to bridge the life-expectancy gap between the general population and multiple myeloma patients.”
Multiple Myeloma: From Front-Line To Relapsed Therapies
Options are increasing rapidly for patients with relapsed multiple myeloma as the number of effective available agents grows, Dr. Moreau said. Among them are three-drug combinations that are demonstrating superiority over two-drug options in relapsed disease and a two-drug strategy superior to lenalidomide alone.
ORR (88% versus 72%) and PFS (18.3 months versus 13.6 months) were better for the triplet of bortezomib, thalidomide, and dexamethasone than for thalidomide and dexamethasone in the Garderet et al. trial of 269 patients with relapsed myeloma. There was also a trend toward higher OS (71% versus 65%, P = 0.09). Grade 3–4 toxicities, however, were higher for the triplet.
In the PANORAMA-1 trial among 768 relapsed patients receiving bortezomib/dexamethasone with or without panobinostat, an ORR trend (60.7% versus 54.6%, P = 0.09) and superior PFS (11.99 months versus 8.08 months; P < 0.0001) favored the triplet. The benefit in median OS for the triplet, however, was not significant (33.6 months versus 30.4 months; P = 0.26). Dr. Moreau noted that all patients had received one to three prior lines of treatment, and only some had received front-line autologous stem-cell transplants (ASCTs). In PANORAMA-1, 58% of the patients were younger than age 65, 56% had received a previous ASCT, and 51% were treated at the time of their first relapse. Again, toxicities (gastrointestinal problems, thrombocytopenia, and fatigue) were higher for the triple combination.
In ASPIRE, adding carfilzomib to lenalidomide and dexamethasone (n = 792) led to significantly higher ORR (87.1% versus 66.7%; P < 0.001) than lenalidomide/dexamethasone, as well as longer PFS (26.3 months versus 17.6 months; P = 0.0001), and greater OS (73.3% versus 65%; P = 0.04). In addition, health-related quality of life was better among patients receiving triplet therapy.
Regarding combination therapies, Dr. Moreau concluded, “Triplet combinations at first relapse probably will become standard in the near future.” He cautioned, however, that the benefits in ORR and PFS will have to be balanced with cost and toxicity.
Dr. Moreau also cited the phase 3 ELOQUENT-2 trial, presented at this year’s ASCO meeting, which compared elotuzumab plus lenalidomide to lenalidomide monotherapy. Two-year PFS for the combination versus lenalidomide was 41% versus 27% (HR, 0.70; 95% CI, 0.57–0.85; P = 0.0004). The elotuzumab/lenalidomide benefits were consistent across subgroups, and the combination was well tolerated with a manageable safety profile. Dr. Moreau pointed out that elotuzumab lacks activity in relapsed melanoma as a single agent. He also named daratumumab, a monoclonal antibody targeting CD38, as showing impressive activity in early testing. As a single agent in advanced patients, it demonstrated an ORR of 30%. It is being evaluated in the phase 3 POLLUX trial.
Dr. Moreau concluded, “Our task will be to define the optimal sequence of treatment, the optimal combinations both for front-line and relapsed myeloma, according to age, comorbidities, cost, drug availability, and patients’ choice.”
SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 ± Bevacizumab Versus mFOLFOX6 + Selective Internal Radiation Therapy (SIRT) ± Bevacizumab in Patients With Metastatic Colorectal Cancer
Among metastatic colorectal cancer patients with liver- dominant metastases, hepatic disease progression was reduced by 31% when selective internal radiation therapy (SIRT) was added to a FOLFOX-based first-line chemotherapy regimen. While overall PFS was not improved by adding SIRT, Ricky Sharma, MD, of Oxford University, the ASCO-designated discussant for the SIRFLOX trial, called the benefit “an impressive change in local control.” He cautioned that AEs were increased, however.
The international, multicenter, open-label, randomized controlled SIRFLOX trial enrolled chemotherapy-naïve patients with nonresectable liver-only, or liver-dominant (liver plus lung and/or lymph-node metastases) metastatic colorectal cancer. SIRT was delivered to the liver with yttrium-90 resin microspheres (Sirtex) via a hepatic artery injection. With Sirtex, liver tumors receive a single, large radiation dose over three weeks. The Food and Drug Administration (FDA) approved Sirtex for treatment of colorectal cancer liver metastases in 2002.
Dr. Gibbs noted that despite several decades of work with other liver-directed therapies, uncertainty remains about their clinical utility because large phase 3 randomized controlled trials are lacking. Liver metastases are the dominant disease site in metastatic colorectal cancer and the predominant cause of death. The combination of chemotherapy plus a biologic is standard first-line therapy for palliative treatment of metastatic colorectal cancer.
Patients in the two treatment arms received either modified (m)FOLFOX6 plus or minus bevacizumab (n = 263) or mFOLFOX6 plus Sirtex administered once with cycle 1 plus or minus bevacizumab until disease progression (n = 267). The primary endpoint was PFS. The presence of extrahepatic disease was one of the stratification factors. Patients’ mean age was 63 years; about a third were female. Forty percent had extrahepatic metastases, and about 90% had synchronous metastases. The primary tumor was removed in about 45% of patients.
Assessment of PFS at any site revealed no differences between groups (10.2 months for FOLFOX plus bevacizumab; 10.7 months for FOLFOX plus bevacizumab plus SIRT; P = 0.43). PFS in liver-dominant cases, however, was 12.6 months for FOLFOX plus bevacizumab and 20.5 months for FOLFOX plus bevacizumab plus SIRT (HR, 0.69; 95% CI, 0.55–0.90; P = 0.002), a 7.9-month improvement.
The ORR, although modestly higher overall for the SIRT arm (76.4% versus 68.1%; P = 0.113), was significantly higher in the liver (72.7% versus 66.9%; P = 0.042). In addition, the complete response rate overall displayed a trend for improvement in the SIRT-containing arm (4.5% versus 1.5%, P = 0.054), but in the liver was significantly higher (6.0% versus 1.9%; P = 0.020).
“Adverse events had no negative impact on duration of systemic therapy and were acceptable and as predicted,” Dr. Gibbs stated. Adverse events (grade 3 or higher) were significantly increased in the SIRT arm versus the FOLFOX plus or minus bevacizumab arm for neutropenia (40.7% versus 28.5%), febrile neutropenia (6.1% versus 1.9%), and thrombocytopenia (9.8% versus 2.6%). Gastric or duodenal ulcers and ascites were also higher for the SIRT group.
Dr. Sharma speculated that the failure to achieve an overall PFS advantage with Sirtex in SIRFLOX was likely attributable to inclusion of 40% of patients with extrahepatic disease. “But there is an impressive change in local control in the liver … so this is a robust result.”
Underscoring the need for more therapies, Dr. Sharma said that despite the FDA approval of 71 drugs for solid cancers between 2002 and 2014, improvements in median PFS and median OS have been only 2.5 and 2.1 months, respectively.
Ibrutinib Combined With Bendamustine and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: First Results From a Randomized, Double-Blind, Placebo-Controlled, Phase III Study
The goal of post-relapse therapy in chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL), because both remain incurable, is to control the disease and provide long, durable remission. Ibrutinib, a first-in-class oral agent targeting Bruton’s tyrosine kinase (BTK), an important protein within the CLL cell, blocks BTK and inhibits cancer cell survival, Dr. Chanan-Khan said in an ASCO press conference.
In the phase 3 HELIOS trial evaluating bendamustine/rituximab with and without ibrutinib, CLL/SLL patients received six or fewer cycles of bendamustine/rituximab and were randomized 1:1 to ibrutinib (420 mg daily, n = 289) or placebo (n = 289). The primary endpoint was PFS assessed by an independent review committee. Secondary endpoints included OS and ORR. Patients in the bendamustine-plus-placebo group could cross over to ibrutinib after disease progression (n = 90).
Median PFS was not yet reached in the ibrutinib-plus- bendamustine/rituximab group and was 13.3 months in the bendamustine/rituximab-plus-placebo group (HR, 0.203; 95% CI, 0.150–0.276; P < 0.0001) after a median follow-up of 17 months. “The combination of ibrutinib plus bendamustine/rituximab significantly reduced the risk of progression or death by 80% as compared with placebo plus bendamustine,” Dr. Chanan-Khan said.
The ORR was significantly higher with ibrutinib plus bendamustine/rituximab versus placebo plus bendamustine/rituximab (82.7% versus 67.8%), and the risk of death was reduced by 37% (P = 0.0598). These benefits were observed despite the fact that 90 patients (31%) with confirmed progressive disease in the placebo-plus-bendamustine/rituximab group crossed over to receive ibrutinib, which confounds the OS results, Dr. Chanan-Khan emphasized.
In the ibrutinib group, disease-related fatigue improved and patients reported benefits sooner (six months versus 14 months) than in the placebo group.
AE incidence was similar in both groups. The rate for neutropenia was 58.2% and 54.7% in the ibrutinib and placebo arms, respectively; nausea was 36.9% and 35.2%. Safety profiles, Dr. Chanan-Khan said, were consistent with the known individual safety profiles for ibrutinib and bendamustine/rituximab.
Dr. Chanan-Khan concluded that adding ibrutinib to bendamustine/rituximab is superior to the current standard of care, bendamustine/rituximab.