Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy.
We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life.
Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand–foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons).
Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib
Bruton’s tyrosine kinase (BTK) is a mediator of the B-cell–receptor signaling pathway implicated in the pathogenesis of B-cell cancers. In a phase 1 study, ibrutinib, a BTK inhibitor, showed antitumor activity in several types of non-Hodgkin’s lymphoma, including mantle-cell lymphoma.
In this phase 2 study, we investigated oral ibrutinib, at a daily dose of 560 mg, in 111 patients with relapsed or refractory mantle-cell lymphoma. Patients were enrolled into two groups: those who had previously received at least 2 cycles of bortezomib therapy and those who had received less than 2 complete cycles of bortezomib or had received no prior bortezomib therapy. The primary end point was the overall response rate. Secondary end points were duration of response, progression-free survival, overall survival, and safety.
The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.
Ibrutinib shows durable single-agent efficacy in relapsed or refractory mantle-cell lymphoma.
Icotinib, an oral EGFR tyrosine kinase inhibitor, had shown antitumour activity and favourable toxicity in early-phase clinical trials. We aimed to investigate whether icotinib is non-inferior to gefitinib in patients with non-small-cell lung cancer.
In this randomised, double-blind, phase 3 non-inferiority trial we enrolled patients with advanced non-small-cell lung cancer from 27 sites in China. Eligible patients were those aged 18—75 years who had not responded to one or more platinum-based chemotherapy regimen. Patients were randomly assigned (1:1), using minimisation methods, to receive icotinib (125 mg, three times per day) or gefitinib (250 mg, once per day) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, analysed in the full analysis set. We analysed EGFR status if tissue samples were available. All investigators, clinicians, and participants were masked to patient distribution. The non-inferiority margin was 1·14; non-inferiority would be established if the upper limit of the 95% CI for the hazard ratio (HR) of gefitinib versus icotinib was less than this margin. This study is registered with ClinicalTrials.gov, number NCT01040780, and the Chinese Clinical Trial Registry, number ChiCTR-TRC-09000506.
400 eligible patients were enrolled between Feb 26, 2009, and Nov 13, 2009; one patient was enrolled by mistake and removed from the study, 200 were assigned to icotinib and 199 to gefitinib. 395 patients were included in the full analysis set (icotinib, n=199; gefitinib, n=196). Icotinib was non-inferior to gefitinib in terms of progression-free survival (HR 0·84, 95% CI 0·67—1·05; median progression-free survival 4·6 months [95% CI 3·5—6·3] vs 3·4 months [2·3—3·8]; p=0·13). The most common adverse events were rash (81 [41%] of 200 patients in the icotinib group vs 98 [49%] of 199 patients in the gefitinib group) and diarrhoea (43 [22%] vs 58 [29%]). Patients given icotinib had less drug-related adverse events than did those given gefitinib (121 [61%] vs 140 [70%]; p=0·046), especially drug-related diarrhoea (37 [19%] vs 55 [28%]; p=0·033).
Icotinib could be a new treatment option for pretreated patients with advanced non-small-cell lung cancer.
For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention.
In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety.
After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower.
Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival.
|Progression-free survival was superior with bevacizumab plus pemetrexed versus bevacizumab alone after induction with bevacizumab, cisplatin, and pemetrexed.|
|Maintenance therapy has been shown to improve survival in patients with non–small-cell lung cancer (NSCLC). Recently, maintenance with single-agent pemetrexed versus placebo was associated with improved progression-free survival (PFS) and overall survival . To test a dual-maintenance strategy in this setting, investigators conducted an industry-supported, phase III, multicenter, randomized, open-label trial (AVAPERL) of maintenance bevacizumab with or without pemetrexed.
A total of 376 patients with advanced, nonsquamous NSCLC received induction therapy with intravenous bevacizumab (7.5 mg/kg), cisplatin (75 mg/m2), and pemetrexed (500 mg/m2) every 3 weeks for 4 cycles. The 253 responding patients were randomized to maintenance bevacizumab every 3 weeks or combination bevacizumab (7.5 mg/kg) plus pemetrexed (500 mg/m2) every 3 weeks.
At a median follow-up of 8.1 months, PFS from time of randomization (the primary endpoint) was superior with combination bevacizumab plus pemetrexed versus bevacizumab alone (median, 7.4 vs. 3.7 months; hazard ratio, 0.48; P<0.0001), as was PFS from time of induction (10.2 vs. 6.6 months; HR, 0.50; P<0.001). OS favored combination therapy but did not reach statistical significance. No new safety signals were identified, but toxicity was greater with combination therapy.
At ASC0 2013, updated results from the AVAPERL trial (Abstract 8014) indicated that OS also failed to reach statistical significance (median OS from randomization, 17.1 vs. 13.2 months; HR 0.87; P=0.29 and median OS from induction, 19.8 vs. 15.9 months; HR 0.88; P=0.32). The AVAPERL trial thus suggests that adding pemetrexed to maintenance bevacizumab improves PFS with a trend towards OS benefit. However, other randomized, phase III data presented at ASCO 2013 (Abstract 8004) indicate that dual maintenance provides no OS benefit. At present, the issue of optimal maintenance therapy in unselected nonsquamous NSCLC patients remains unknown. Treatment decisions are currently based on eligibility for bevacizumab treatment and patient preference for toxicity profiles.
After standard chemotherapy, maintenance therapy with sunitinib delayed relapse by approximately 1.5 months compared with placebo for patients with extensive-stage small cell lung cancer (SCLC), according to new findings from a phase II trial.
Dr. Neil Ready, MD, PhD, of the Duke Cancer Institute in Durham, North Carolina, presented results from the randomized, phase II Cancer and Leukemia Group B (CALGB) 30504 trial (Ready N et al., 2013) at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois.
Sunitinib is an oral, multitargeted receptor tyrosine kinase (RTK) inhibitor that shows potent and selective activity against vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and other molecular targets implicated in tumor growth and angiogenesis. Sunitinib is currently approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. Although sunitinib and other RTK inhibitors have been studied extensively in non-small cell lung cancer (NSCLC) (Gridelli C et al.), few studies have examined sunitinib in SCLC.
CALGB 30504 Study Design
The CALGB 30504 trial began in 2007 as a phase I trial of concurrent therapy with sunitinib and standard chemotherapy in untreated extensive-stage SCLC. The concurrent regimen was not feasible, however, due to the risk of grade 5 neutropenia (Ready N et al., 2010). In 2008, the CALGB 30504 protocol was amended to a randomized phase II trial designed to evaluate maintenance sunitinib following chemotherapy. In the current analysis, 85 patients received 4-6 cycles of standard-dose chemotherapy with cisplatin/etoposide or carboplatin/etoposide every 21 days. Patients were randomly assigned to maintenance therapy with sunitinib 37.5 mg/day (n = 44) or placebo (n = 41) until disease progression. Crossover to sunitinib maintenance was permitted in the placebo arm at disease progression.
The median patient age was 60 years (range, 39-77 years). The majority of patients (76.5%) completed 6 cycles of chemotherapy; 26% received cisplatin and 74% received carboplatin. Among patients with a complete or partial response (n = 78), 34 patients (44%) received prophylactic cranial irradiation 4 to 6 weeks after completing chemotherapy.
Patients completed a median of two cycles of maintenance therapy (range, one to 17 cycles). In the sunitinib arm, 68% of patients completed 1 to 4 cycles, while 23% completed 5 to 8 cycles. Four patients (9%) completed 9 or more cycles of sunitinib maintenance. The crossover rate was high, with 40% of patients in the placebo group initiating sunitinib following disease progression.
Improved Progression-Free Survival
The CALGB 30504 trial met its primary endpoint of improved progression-free survival after chemotherapy with maintenance sunitinib. The median progression-free survival was 3.77 months in the sunitinib maintenance group, compared with 2.30 months in the placebo group (HR, 1.53; P = 0.037).
Despite the high crossover rate, maintenance sunitinib showed a trend toward improved overall survival compared with placebo. The median overall survival was 8.95 months in the sunitinib group and 6.89 months in the placebo arm (HR, 1.17; P = 0.27).
Evidence of Single-Agent Activity
An analysis of tumor size before and after crossover to sunitinib in six patients with disease progression in the placebo group also demonstrated the single-agent antitumor activity of sunitinib. In the 6 to 12 weeks prior to crossover, the tumors were exhibiting rapid growth. Following crossover to sunitinib, tumor growth slowed in each case, and some tumors decreased in size.
In another case, the pattern of tumor response during chemotherapy and maintenance provided additional support for single-agent activity with sunitinib. The patient showed a partial response to chemotherapy, which plateaued between cycles 4 and 6, but converted to a complete response during sunitinib maintenance. The complete response was maintained without progression for 15 cycles (45 weeks) of maintenance therapy.
Maintenance sunitinib appeared safe and feasible at this dose. During maintenance, 46.5% of patients in the sunitinib group reported at least 1 grade 3/4 adverse event, compared with 19.5% of patients in the placebo group. The most common grade 3/4 adverse events during sunitinib maintenance were fatigue (19%), neutropenia (14%), leukopenia (7%), thrombocytopenia (7%), and hyponatremia (5%). Grade 4 events included gastrointestinal hemorrhage (n = 1) and pancreatitis (n = 1).
A biomarker analysis of blood samples is being planned, with the goal of identifying prognostic and predictive markers that may guide the selection of patients for maintenance therapy. A randomized phase III trial is being proposed to test the hypothesis that maintenance sunitinib after standard chemotherapy improves survival in patients with extensive-stage SCLC.
Dr. Ready explained the rationale for additional studies of maintenance sunitinib. “We felt that the [phase II] results were consistent with the hypothesis that there could be a 2-month or more improvement in overall survival with maintenance sunitinib in this setting. We feel that it is reasonable to consider a phase III trial to test that hypothesis,” Dr. Ready said.
Source: The oncologist
Current and Future Options for Targeting Activated Kinases in Acute and Chronic Leukemias
Contributors: Anna Azvolinsky, PhD, Anne Jacobson, MPH, CCMEP, CMPP
Tyrosine kinase oncogenes such as BCR-ABL and FLT3 are commonly mutated and activated in acute and chronic myeloid leukemias. The development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myelogenous leukemia (CML) and provided new treatment options for patients with chronic myeloproliferative neoplasms and acute leukemias. In a special session at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting on the role of targeted therapy in acute and chronic leukemias, experts discussed the current clinical issues and future opportunities associated with the targeted inhibition of aberrant signaling pathways that drive the development and progression of these malignancies.
Resistance to BCR-ABL-targeted therapy in patients with CML arises through an array of potential mechanisms, ranging from non-specific multidrug resistance to inherent BCR-ABL genetic alterations. Michael J. Mauro, MDof the Knight Cancer Institute, Oregon Health & Science University, in Portland, Oregon, discussed targeted approaches to managing treatment resistance in patients with CML.
In 2001, the approval of imatinib, the BCR-ABL kinase inhibitor, launched a new area of targeted therapy for CML. Imatinib has been so successful that it has grown to become the targeted therapy all other therapies want to emulate—oncologists often aspire to finding the “imatinib” of other cancer types. As of 2013, five targeted agents are currently available for CML, including two agents, bosutinib and ponatinib, that joined the salvage treatment armamentarium in 2012.
After more than a decade of experience with imatinib in CML, the oncology community has gained critical insight about the development and progression of treatment resistance, with potential implications for other targeted therapies. Importantly, resistance to imatinib is a function both of time and disease volume. Early reduction of disease burden is associated with the reduction or elimination of unstable clones, leading to a reduction in the risk of relapse. Timely cytogenetic and molecular response is a strong predictor of functional cure, which is defined as the absence of meaningful proliferation even after treatment is stopped.
Options for patients who show early resistance to imatinib (e.g., BCR-ABL/ABL >10% at 3 months) include switching to another tyrosine kinase inhibitor based on mutational analysis, evaluating candidacy for stem cell transplant, or referring the patient to a clinical trial. Ongoing trials will evaluate the utility of various approaches to early resistance, including immediate versus delayed switch to an alternate targeted regimen. Treatment selection is further individualized based on a tolerability profile and likelihood of treatment adherence. Among current options, nilotinib, dasatinib, and bosutinib are proven salvage options with promising activity in the front-line setting. Ponatinib also represents a compelling salvage option, particularly for patients with heavily pretreated CML who have stopped responding to all other therapies. A phase III trial comparing ponatinib with imatinib in patients with newly diagnosed chronic-phase CML is currently underway.
Chronic Myeloproliferative Neoplasms
Targeted therapy is rapidly changing the treatment landscape for chronic myeloproliferative neoplasms, including primary myelofıbrosis (MF), essential thrombocytopenia (ET), and polycythemia vera (PV). Following the identification of the JAK2V617F mutation in 2005, the first JAK1/2-targeted therapy was approved just six years later, in 2011. Claire Harrison, DM of the NHS Foundation Trust in the UK, discussed the current standard of care for primary MF, post-ET/PV MF, and other myeloproliferative neoplasms in the era of JAK1/2 inhibitor therapy.
Ruxolitinib was the first oral, selective JAK1/2 inhibitor approved for the treatment of intermediate- and high-risk MF, based on substantial reduction in spleen size and improvements in other constitutional symptoms and quality of life in the phase III COMFORT-1 and COMFORT-2 trials. To date, treatment with ruxolitinib has not resulted in any molecular remissions, although there is hope for the concept of a ‘cure’ with targeted therapy alone. In current practice, allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with MF. Other limitations of current systemic treatment options in MF include concerns about the induction of leukemia as well as the inability to reduce late myeloid transformation.
Building on the success of ruxolitinib, other JAK-targeted inhibitors in development include SAR302503, a selective JAK2 inhibitor; pacritinib, an oral, once-daily, highly selective inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3); and CYT387, an oral JAK1/2 inhibitor. Future clinical trials in this setting may focus on regimens designed to improve the hematologic toxicity profile of current JAK1/2 inhibitor therapy or improve treatment efficacy via the use of novel JAK1/2 inhibitors alone or in combination with other targeted agents, such as histone deacetylase (HDAC), phosphatidylinositol 3 (PI3)-kinase, and smoothened pathway inhibitors.
Advances in the molecular profiling of acute leukemia, particularly the role of activating mutations that result in signaling molecule alterations, may introduce new opportunities for targeted therapy. Neil Shah, MD, PhD of the University of California, San Francisco, discussed the evolving rationale for kinase inhibition in the treatment of acute leukemia.
Acute leukemia is frequently associated with activating mutations in signaling molecules. Kinase inhibitors provide an effective, well-tolerated tool to substantially reduce the burden of disease and, when combined with chemotherapy, improve cure rates in patients with acute myeloid leukemia (AML). The number of possible combination regimens with other targeted agents is growing as novel pathway inhibitors are being developed. Performing detailed molecular analyses of tumor samples is becoming more feasible, and promises to facilitate the personalized selection of rational targeted therapies and combination regimens in the near future.
Several kinase inhibitors are in development for AML, but early stage results lag behind the advances seen in the CML setting. Many of the targeted multikinase inhibitors currently under development in AML may have a role as bridge therapy, providing patients the time to transition to a potentially curative stem cell transplant.
The key obstacle in the development of targeted agents for AML is a lack of a known dominant driver mutation. The most common mutation appears to be a tandem repeats of the activating mutations of the FLT3 receptor tyrosine kinase in about a quarter of patients. Agents such as quizartinib and crenolanib are in clinical trials, but rapid relapse is common. “FLT3 may be a passenger rather than a driver mutation [in AML] and not worth targeting,” saidDr. Shah. Inhibitors of KIT, JAK2, mTOR, and MEK are also under evaluation in AML, but their potential antitumor activity in patients who do not harbor mutated kinases is unknown.
Incorporating next-generation molecular sequencing tools into studies of targeted therapeutics will advance the use of personalized treatment in acute leukemia. Continued participation of patients with AML and other malignancies in clinical trials is strongly encouraged, Dr. Shah said.
Source: The oncologist
Inhibition of the mammalian target of rapamycin (mTOR) is important for overcoming endocrine resistance in ER-positive breast cancer, and positive results from the BOLERO-2 trial (N Engl J Med 2012 Feb 9; 366:520) led to the approval of the mTOR inhibitor everolimus in combination with exemestane for patients who develop progressive disease after treatment with a nonsteroidal aromatase inhibitor. The importance of the mTOR signaling pathway is not restricted to endocrine-sensitive breast cancer. Preclinical data suggest that targeting human epidermal growth factor receptor-2 (HER2) and mTOR may overcome trastuzumab resistance.
Now, O’Regan and colleagues have conducted the multicenter, phase III, randomized, controlled, double-blind BOLERO-3 trial (Abstract 505) to evaluate the combination of the mTOR inhibitor everolimus, the chemotherapy agent vinorelbine, and the HER2 inhibitor trastuzumab versus vinorelbine and trastuzumab in 569 patients with HER2-positive advanced breast cancer; 84% of patients received trastuzumab in the metastatic disease setting and developed disease progression, whereas 16% developed disease progression while receiving adjuvant trastuzumab or within 12 months of receiving it. Patients could have received up to three treatment regimens for metastatic disease; 27% of patients received prior lapatinib.
The inclusion of everolimus conferred a significant improvement in progression-free survival (7.0 vs. 5.8 months; P=0.0067) but no improvement in rates of overall survival (at current follow-up), objective response, or clinical benefit. The addition of everolimus to chemotherapy (5 mg daily) was associated with toxicities similar to that seen when everolimus was combined with the AI exemestane: stomatitis, fatigue, rash, hyperglycemia, and rare pneumonitis.
The combination of everolimus, vinorelbine, and trastuzumab may provide yet another option for patients with HER2-positive metastatic breast cancer. But, if approved, it will likely be positioned after both first-line trastuzumab, pertuzumab, and a taxane and second-line trastuzumab emtansine (T-DM1; JW Oncol Hematol Feb 26 2013). Other treatment considerations in this space include lapatinib and capecitabine, alternative trastuzumab/chemotherapy combinations, and the combination of trastuzumab and lapatinib.
EGFR overexpression occurs in 27—55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.
In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1—21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1—21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785.
Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6—13·0) compared with 8·8 months (7·7—9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07—1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3—4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]).
Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.
The REAL3 trial is one of two concurrent randomised phase 3 trials (the other being the EXPAND trial15) assessing the addition of anti-EGFR monoclonal antibodies to chemotherapy in first-line oesophagogastric cancer. Based on the findings of REAL3, use of panitumumab in combination with EOC cannot be recommended in an unselected population with advanced oesophagogastric adenocarcinoma, and was associated with inferior overall survival and PFS. Notably, this detrimental outcome in the experimental group was not predicted by the phase 2 endpoint of response rate (overall response rate 52% with mEOC+P). This trial does, however, confirm the efficacy of the EOC control group in this setting, with median overall survival and PFS results that are consistent with those previously reported in REAL2 (11·2 months for overall survival and 7·0 months for PFS).3
The poor outcome associated with mEOC+P in this trial did not seem to be attributable to increased treatment-related deaths, and therefore other potential explanations for our findings need to be considered. First, as reported previously,12combination of panitumumab with full-dose EOC in the initial stages of the trial was associated with unacceptably high rates of grade 3 diarrhoea (four of the first five patients by cycle four). Therefore, we had to reduce the starting doses of oxaliplatin (by 23%) and capecitabine (by 20%) in the experimental group. Although these changes undoubtedly reduced the frequency of grade 3—4 diarrhoea with mEOC+P (17% in phase 3 population), they also served to reduce the dose intensity of chemotherapy, which is reflected in the reduced incidence of grade 3—4 neutropenia and peripheral neuropathy noted in the mEOC+P group. Additionally, the dose intensity data show a reduced proportion of patients achieving at least 80% of the planned capecitabine dose in the experimental group, suggesting that mEOC+P was still slightly more difficult to deliver than standard EOC.
Second, a negative interaction might have occurred between panitumumab and one or more of the EOC components. Evidence in the setting of colorectal cancer suggests that the chemotherapy partner for anti-EGFR therapy might be an important determinant of treatment efficacy, with oxaliplatin-containing regimens yielding inconsistent results. The OPUS16and PRIME11 studies provide evidence of improved outcomes with the addition of cetuximab and panitumumab respectively, whereas no benefit was associated with the addition of cetuximab in the COIN17 and NORDIC VII18 studies in the same setting. Recent cell-line data also suggest that greater synergy might exist between anti-EGFR therapy and irinotecan than with oxaliplatin.19 Additionally, the COIN trial17 results suggest that there might be a differential benefit from cetuximab dependent on the fluoropyrimidine partner, with patients receiving oxaliplatin plus fluorouracil seemingly deriving increased benefit compared with those treated with oxaliplatin plus capecitabine. At present, the significance of these potential interactions is unknown, and has not been assessed in the setting of oesophagogastric cancer.
Third, our findings might have been affected because we assessed panitumumab therapy in a molecularly unselected population. During the years since the inception of the REAL3 trial, several studies have advanced our understanding of the EGFR signalling pathway and its role in oesophagogastric adenocarcinoma. Hot-spot mutations in key oncogenic drivers such as KRAS (common in colorectal cancer) and BRAF (common in malignant melanoma) are now known to be infrequent molecular events in oesophagogastric adenocarcinoma. Indeed, the 5·7% frequency of KRAS mutation in our population is in keeping with the 3—10% reported in other studies,20—22 and we did not note any BRAF mutations in 167 tumour samples tested. By contrast, gene copy number alterations (amplifications and deletions) seem to be a relatively frequent finding in oesophagogastric adenocarcinoma and are more likely to represent the key molecular alterations driving carcinogenesis. Two recent series23, 24 of detailed genomic analyses in oesophagogastric adenocarcinoma reported that about 37% of tumours harbour copy number aberrations in genes that are deemed to be targetable, including KRAS, EGFR, HER2, and MET. Randomised clinical trials are therefore needed to establish whether targeting of these oncogenic signal transduction pathways can meaningfully improve outcomes for patients.
In preclinical studies, cetuximab can decrease EGFR pathway signalling via reduced phosphorylation of EGFR and AKT in oesophagogastric cancer cell lines.25 In combination with chemotherapy, cetuximab results in synergistic inhibition of cell proliferation and enhanced apoptosis.25—27 In hypoxic gastric cancer cell lines the addition of anti-EGFR therapy reversed oxaliplatin resistance.26 Additionally, a synergistic antitumour effect of combined cetuximab and S-1 was apparent in gastric cancer cell lines overexpressing EGFR.25, 27 In colorectal cancer, somatic mutations in codon 12, 13, or 61 of the KRASoncogene confer resistance to panitumumab therapy.11, 28 MET amplification with or without KRAS mutations might be associated with resistance to cetuximab therapy in gastric cancer cell lines;29 however, no validated predictive biomarkers for this setting exist.
Unfortunately, despite preclinical data suggesting a role for anti-EGFR therapy in the treatment of oesophagogastric adenocarcinoma, the REAL3 trial findings are supported by two other phase 3 trials assessing anti-EGFR therapy in this disease setting. The EXPAND trial15 assessed the addition of cetuximab to a cisplatin-capecitabine doublet in 904 patients with previously untreated adenocarcinoma of the stomach and gastro-oesophageal junction, and did not meet its primary endpoint of improved PFS (HR 1·09, 95% CI 0·92—1·29, p=0·32).15 EXPAND also noted no improvement with the addition of cetuximab in either overall survival (HR 1·00, 95% CI 0·87—1·17, p=0·95) or overall response rate (30% in the experimental group vs 29% for controls). The COG trial30 assessed the anti-EGFR tyrosine-kinase inhibitor gefitinib compared with placebo in the second-line treatment of 450 patients with oesophageal and type I—II gastro-oesophageal junction cancers. This trial also did not meet its primary endpoint, with no improvement in overall survival (HR 0·90, p=0·285). However, improvements in PFS (HR 0·795, p=0·017) and disease control at 8 weeks (25·5% in the experimental group vs 16·0% in controls, p=0·014) were noted, suggesting some activity of gefitinib in a small undefined subset of patients.
Taken together, these relatively consistent findings suggest that the EGFR pathway is unlikely to represent an important therapeutic target in most patients with oesophagogastric cancer (panel). The presented biomarker analyses accompanying the REAL3 trial are restricted by small patient numbers and low rates of tested mutations. However, this work is ongoing in the full trial dataset and these translational analyses represent a unique opportunity to further assess the molecular biology of advanced oesophagogastric adenocarcinoma within a randomised trial setting. Techniques such as gene-expression profiling and next-generation sequencing might help to provide further information regarding the driver genetic events in this complex disease. Furthermore, the evaluation of genetic aberrations in pathways linked to EGFR signalling could still offer the prospect of identification of a low-frequency biomarker that identifies a subpopulation of patients benefiting from anti-EGFR targeted therapy in this setting.
Several drugs targeting VEGF or mTOR pathways have been approved for treatment of advanced renal-cell carcinoma because of improvements noted in progression-free survival (PFS) in phase 3 trials.1 Validation of prognostic models showed that treatment with such drugs can lead to a median overall survival of around 43 months for patients in favourable risk categories and 23 months for patients in intermediate risk categories.2 With few exceptions, patients on first-line therapy progress and proceed to need one or more subsequent lines of targeted therapy. In a population-based study,3 patients in a favourable risk group had progression on first-line VEGF-targeted therapy after a median of 16·6 months (compared with 15 months for patients in an intermediate risk group) and progression after 6·2 months on second-line targeted therapy (5·5 months for intermediate risk). Two phase 3 trials4, 5 assessed outcomes after failure of a previous VEGF-targeted therapy to establish evidence for the mTOR-inhibitor everolimus and the selective inhibitor of VEGF receptors 1—3, axitinib. The AXIS trial5 is the only study that directly compared two active compounds (axitinib vs sorafenib) after failure of an approved first-line regimen. In AXIS, more than a third of patients had received cytokines and over half had received sunitinib as first-line therapy. Axitinib led to an improvement in median PFS compared with sorafenib in the intention-to-treat analysis. However, the difference in PFS for patients after sunitinib treatment based on investigator and independent review committee assessments was only slight. Data for overall survival, a secondary endpoint, were immature before the first report was published in 2011. Because guidelines and clinical practice favour targeted therapy in preference to cytokines as first-line treatment,1 axitinib is regarded as a treatment option for second-line therapy of advanced renal-cell carcinoma.5
In The Lancet Oncology, Robert Motzer and colleagues6 now report mature overall survival data for the AXIS trial. Such an analysis is important because crossover between the two study arms was not allowed. No significant differences in overall survival were noted between patients in both treatment arms who received the same first-line regimen (median overall survival 20·1 months [95% CI 16·7—23·4] with axitinib vs 19·2 months [17·5—22·3] with sorafenib; hazard ratio 0·969, 95% CI 0·800—1·174, p=0·3744). More than half the patients in each arm continued with a third-line treatment after progression on study drug and treatment after progression was allowed. This design confounded overall survival results and raises questions as to whether PFS is meaningful in this setting.7 Third-line therapy partly explains the long time interval noted between progression on second-line treatment and overall survival. However, inclusion of patients with a less aggressive tumour biology might have contributed to this outcome. Only a third of patients in the AXIS trial were Memorial Sloan Kettering Cancer Center (MSKCC) poor risk at entry,5 suggesting that individuals with rapid deterioration of performance or accelerated progression during first-line therapy are less likely to enter trials than are patients with more favourable risk profiles.
For patients previously treated with sunitinib in Motzer and colleagues’ study,6 median time on first-line therapy was about 10 months, with a median overall survival for all risk groups of 15·2 months (95% CI 12·8—18·3) for axitinib and 16·5 months (13·7—19·2) for sorafenib. Patients who received cytokines had first-line therapy for about 6 months and a median overall survival of 29·4 months (24·5—not assessable) for axitinib and 27·8 months (23·1—34·5) for sorafenib. After correction for the different length of first-line therapies, overall survival seemed to be increased by about 7—9 months in patients who had cytokines before VEGF-targeted therapy. Resistance to previous VEGF-targeted therapy, which might not be apparent in patients previously untreated with such an approach, cannot fully explain this difference. Motzer and colleagues noted a putative association of overall survival with length of previous sunitinib treatment for both axitinib and sorafenib, although there was substantial overlap in the 95% CIs.6 A retrospective Database Consortium analysis of 464 patients who had received two lines of VEGF-targeted therapies reported no correlation between first-line PFS and second-line PFS.8 Rather, a significant difference in multivariate analysis of baseline prognostic factors in favour of cytokine versus sunitinib pretreatment (HR 0·503, 95% CI 0·395—0·641; p<0·0001) suggested that patients with less advanced disease were most likely to start treatment with cytokines.6 However, information about the distribution of prognostic factors between patients who were pretreated with cytokines and sunitinib, which could have important implications for treatment sequences, is not provided in Motzer and colleagues’ study.
Data from trials and population-based analyses suggest that a ceiling has almost been reached in terms of outcome with present targeted therapies and prognosis that relies on models based on clinical factors.2 The mature AXIS data add axitinib to the choices for second-line treatment with similar outcome and different toxicity profiles.4—6 Despite prognostic factors assessed in the updated analysis and a correlation of development of hypertension during axitinib and sorafenib treatment with overall survival, the choice for a second-line drug or even treatment beyond progression at failure of first-line treatment remains an educated guess. The outcome of this study proves once again that renal-cell carcinoma is a heterogenous cancer9 that needs further research into predictive biomarkers to tailor treatment choices.