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Abstract

The move towards personalized medicine is ongoing with exciting research being conducted across all areas of oncology. The evidence presented at the 2012 European Society of Medical Oncology Congress (Vienna, 28 September–2 October 2012) adds to the move towards selecting patients for specific drug treatments based on elucidating biomarkers that reveal susceptible mutations or pathways. Epidermal growth factor receptor (EGFR) and KRAS mutations are well-known examples of this approach, and evidence presented at the congress corroborated this strategy across many cancer types: for example, the efficacy of tivantinib in MET-positive patients with hepatocellular carcinoma (HCC) [Daniele et al. 2012], crizotinib in anaplastic lymphoma kinase (ALK)-positive patients with nonsmall cell lung cancer (NSCLC) [Shaw et al. 2012], and the combined use of dabrafenib plus trametinib in BRAF V600E mutation-positive and mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor treatment-naïve patients with metastatic melanoma [Long et al. 2012]. Data are also accumulating about the optimal duration of therapy; see the latest results from the Herceptin Adjuvant (HERA) trial and Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trials in breast cancer [Goldhirsch et al. 2012; Pivot et al. 2012], and the use of bevacizumab beyond progression in metastatic colorectal cancer [Masi et al. 2012] reported in this article. This editorial features highlights of late-breaking and best abstracts in medical oncology presented at the conference.

Whole-genome cancer testing shows promising clinical utility

A number of cancer drugs have been developed in recent years that specifically target genetic alterations. Current genetic testing only analyses a limited number of genes; however, Dr Fabrice André and colleagues (Institute Gustave Roussy, Villejuif, France) have tested the entire genome of individual breast cancers in an attempt to better personalize treatment. It may be that whole-genome testing can identify both frequent and rare unexpected genomic events, quantify genomic instability, and detect the driver mutations causing genomic alterations that lead to resistance to targeted agents.

Dr André described the SAFIR01 trial, where a program was developed to analyse prospectively the entire genome from a biopsy of a metastatic lesion from patients with metastatic breast cancer [André et al. 2012]. Array-comparative genomic hybridization and Sanger sequencing allowed them to identify which genes were mutated, amplified or deleted. The resulting genomic information was then used to tailor the most appropriate targeted treatment. To date, they have performed whole genome analysis among 248 of the 402 tested patients and managed to provide a specific targeted treatment in 172 cases; in some cases a very rare or unexpected genomic alteration was found, thus showing the benefit of whole genome analysis.

Dr André believes that whole genome analysis can become part of daily oncology practice because of its simplicity and its ability to provide a broad picture of genomic alterations and to test biomarkers.

HCC

SEARCH: adding erlotinib to sorafenib provides no benefit

The Sorafenib and Erlotinib, a rAndomized tRial protoCol for the treatment of patients with Hepatocellular carcinoma (SEARCH) phase III trial of sorafenib plus erlotinib was designed to see if combining these drugs had any synergistic or additive antitumour efficacy. There were 720 patients with advanced HCC (Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0–1, Child–Pugh class A) enrolled into the study. They randomly received continuous treatment with oral sorafenib (400 mg twice daily) plus erlotinib (150 mg daily) or sorafenib (400 mg twice daily) plus placebo and were monitored every 6 weeks by computerized tomography scans.

Andrew Zhu (Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA, USA) presented the results and showed that overall survival (OS) (primary endpoint) did not differ significantly between the two treatment groups (9.5 months for combined therapy versus 8.5 months in the sorafenib plus placebo group [Zhu et al. 2012]. Similar nonsignificant differences in time to progression (TTP) (secondary endpoint) were also observed (3.2 months versus 4.0 months for erlotinib and placebo groups, respectively). The sorafenib plus erlotinib group also showed trends towards less disease control rates and less treatment duration because of higher withdrawal rates. Treatment-emergent and drug-related adverse events and any serious adverse events were similar between the groups.

Thus, adding erlotinib to sorafenib does not improve OS or TTP over sorafenib alone in patients with advanced HCC. Sorafenib remains the standard treatment in such patients.

This latest result adds to several other disappointing phase III trials of targeted agents in HCC. The SUN trial was discontinued in 2010 after early data showed sunitinib was inferior to sorafenib in terms of OS and was more toxic [Cheng et al. 2011]. In December 2011, the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor targeted agent, brivanib, was reported to show no improvement in OS over placebo when given as second-line therapy in the Brivanib Study in HCC Patients at Risk Post Sorafenib (BRISK-PS) trial [Llovet et al. 2012], and in 2012 the Brivanib Study in HCC Patients at Risk First Line (BRISK-FL) trial of brivanib as first-line therapy also failed to meet its primary OS endpoint [BMS, 2012].

Professor Roberto (Labianca Riuniti Hospital, Bergamo, Italy) commented at the symposium that future trials need to be based on selecting patient populations based on the molecular target profile of the agents being studied, similar to the research with trastuzumab in HER2-positive breast cancer.

Targeted treatment with tivantinib shows potential

Signs that a strategy of selecting patients for specific treatments will be successful were presented by Dr Bruno Daniele (Rummo Hospital, Benevento, Italy) who presented the final results from the phase II trial of second-line tivantinib (ARQ 197, a MET inhibitor) in unresectable HCC. There were 107 patients (PS < 2, Child–Pugh A) randomized in a 2:1 ratio to receive tivantinib or placebo [Daniele et al. 2012]. The median TTP (primary endpoint) showed a small benefit in favour of tivantinib in the overall intent-to-treat population (TTP 6.9 versus 6.0 weeks; hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.43–0.94; p = 0.04). However, efficacy results among MET-positive patients treated with tivantinib were much more robust with median TTP of 11.7 weeks versus 6.1 weeks for placebo (HR 0.43; 95% CI 0.19–0.97; p = 0.03). In the same patient group, disease control rate was 50% versus 20% for placebo and median OS was 7.2 months versus 3.8 months for placebo (HR 0.38; 95% CI 0.18–0.81; p = 0.01). The safety profile was manageable: in MET-positive patients on tivantinib the most common adverse events were fatigue (31.7%) and asthenia (27.3%), and a dose of 240 mg twice daily tivantinib provided efficacy without the degree of neutropaenia seen with a higher starting dose of 360 mg twice daily.

The pronounced activity of tivantinib in MET-positive patients is impressive and has led to the initiation of a phase III trial in MET-positive HCC patients. Confirmation of these results in the phase III trial would verify that personalized medicine is needed in HCC.

Breast cancer

HERA: extending trastuzumab for 2 years is no better than 1 year

The HERA phase III study of 5102 women with early HER2-positive breast cancer is still providing valuable data. After completion of primary therapy (i.e. surgery, chemotherapy and radiotherapy as indicated), patients were randomly assigned to an observation group or to trastuzumab therapy every 3 weeks for 1 or 2 years. Richard Gelber (Harvard Medical School and Dana-Farber Cancer Institute, Boston, MA, USA) and colleagues found that 1-year trastuzumab treatment was as good as 2 years of treatment: unadjusted HR for disease relapse in the 2-year treatment arm versus the 1-year arm was 0.99 (95% CI and p-value). OS in the two arms was also comparable (HR = 1.05; 95% CI 0.86–1.28; p = 0.6333) [Goldhirsch et al. 2012].

Thus, 1 year of trastuzumab treatment remains the standard of care for HER2-positive early breast cancer patients. The researchers also stated that the 8 years of follow-up data of the 1-year adjuvant regimen (compared with no trastuzumab therapy) showed the enduring benefit in disease-free survival (DFS) and centres of the therapy: reduced risk of disease recurrence and death by one-quarter compared with not using trastuzumab.

PHARE trial: 6 months versus 12 months of adjuvant trastuzumab in early breast cancer

The PHARE trial was designed to look at the duration of adjuvant trastuzumab therapy in HER2-positive early breast cancer: the primary objective was DFS in patients who received 6 months versus 12 months adjuvant trastuzumab (noninferiority schema). Over 150 cancer care centres in France took part with more than 3380 patients recruited. Xavier Pivot (Université de Franche Comte, Besancon, France) presented the study results [Pivot et al. 2012].

Median follow up was 42.5 months and 395 centres’ events were reported at time of analysis. The noninferiority design of this trial showed that 6-month trastuzumab was not significantly inferior to 12-month trastuzumab (HR = 1.28; 95% CI 1.04–1.56; p = 0.29; the CI range covered the 1.15 noninferiority margin). The authors suggested that the HR of 1.28 showed there is a trend favouring 12 months’ over 6 months’ therapy. Ongoing analysis among subgroups is being performed. These results, as well as the HERA result above, add to the evidence about delivering an optimal duration of treatment for selected patient populations.

TURANDOT riddle is partly revealed

The phase III Central European Cooperative Oncology Group study on capeciTabine and bevacizUmab Randomized Against avastiN anD taxOl Trial (TURANDOT) compared two bevacizumab-containing regimens as first-line therapy for chemotherapy-naïve patients with HER2-negative metastatic breast cancer. Patients were randomized to placebo or one of two bevacizumab regimens: bevacizumab (10 mg/kg days 1 and 15) plus paclitaxel (90 mg/m² days 1, 8 and 15 every 4 weeks or bevacizumab (15 mg/kg day 1 plus capecitabine 1000 mg/m² twice daily days 1 and 14 every 3 weeks) until disease progression or unacceptable toxicity occurred. Noninferior OS with bevacizumab/capecitabine versus bevacizumab/paclitaxel was the primary endpoint with interim and final OS analyses planned after 175 and 389 deaths, respectively. Christoph Zielinski (Comprehensive Cancer Centre, Vienna, Austria) reported the first efficacy results at the preplanned analysis (19 months) [Zielinski et al. 2012]. Noninferiority in OS was not met at the required level of statistical significance: 1-year OS rate was 81% in 285 patients treated with bevacizumab plus paclitaxel, and 79% in 279 patients receiving bevacizumab/capecitabine (HR = 1.04; −∞ to 1.69; p = 0.0593). With regard to secondary endpoints, the respective response rate in the two arms was 44% and 27% (p = 0.0001) and progression-free survival (PFS) was a median of 11 months and 8.1 months, respectively, in the bevacizumab/paclitaxel and bevacizumab/capecitabine arms (p = 0.0052). Adverse events followed the known safety profiles of all three drugs: grade ≥3 adverse events included neutropaenia (18%), peripheral neuropathy (14%) and leucopoenia (7%) among bevacizumab/paclitaxel patients while hand-foot syndrome (16%), hypertension (6%) and diarrhoea (5%) occurred with bevacizumab/capecitabine. The significantly better PFS and overall response rate with the bevacizumab/paclitaxel regimen but lack of inferiority of bevacizumab/capecitabine with regard to OS is noteworthy given that the comparison of OS between the two study arms was the primary endpoint of the study. Final results are expected in 2014.

NeoALTTO: post-treatment outcome should determine the need for breast-conserving treatment

The Neoadjuvant Lapatinib and/or Trastuzumab Treatment (NeoALTTO) trial [Baselga et al. 2012] showed that neoadjuvant paclitaxel, lapatinib plus trastuzumab significantly increased the pathological complete response rate compared with paclitaxel plus either drug alone in 429 women with HER2-positive breast cancer. Surprisingly, breast-conserving surgery remained around 40% regardless of which treatment the 429 women in the study received. Dr Carmen Criscitiello (European Institute of Oncology, Milan, Italy) and colleagues have analysed the factors that may affect the choice of surgery offered to patients [Criscitiello et al. 2012].

They observed that baseline tumour characteristics prior to neoadjuvant therapy are given the main emphasis in deciding on type of surgery whereas response to therapy is not considered. This basis of determination denies a large proportion of women the chance of preserving their breast. It is not clear what the reason is for neoadjuvant therapy leading to high pathological complete response rates not translating into higher rates of breast conservation. Modern breast cancer surgery needs to orientate its strategy around post-treatment outcome rather than baseline results.

Dr Criscitiello has called for consensus in the role of breast-conserving surgery for patients responding to neoadjuvant therapy.

Lurbinectedin: response in platinum-resistant or refractory ovarian cancer

Lurbinectedin (PM01183) binds the minor groove of DNA and inhibits tumour growth as a result of reduced cell proliferation (due to apoptosis in cells undergoing aberrations during mitosis). Earlier in vitro and in vivo results showed efficacy in ovarian cancer cell lines, including several that display platinum resistance. Thus, investigators surmised that the drug may be effective among the 30% of ovarian cancer patients at relapse who have platinum-resistant or refractory disease.

Dr Dominique Berton-Rigaud (Center René Gauducheau, Nantes, France) presented the first stage of a randomized phase II study of lurbinectedin comprising 22 patients with platinum-resistant or refractory ovarian cancer (35–77 years of age; ECOG PS 0–2; response rate was the primary endpoint) [Berton-Rigaud et al. 2012]. A total of 15 patients had received one prior chemotherapy and 7 had received two previous lines; 6 were classed as platinum refractory and 16 were platinum resistant.

Six patients responded to the drug (two by Rustin and four by Response Evaluation Criteria in Solid Tumours [RECIST] criteria) producing an overall response rate of 27% (95% CI 11−50%); this included one radiological complete response. Progression was observed in six (27%) patients at first evaluation; an overall disease control rate of 73%. The second stage of the trial began in April 2012 and consists of 60 patients who have received either lurbinectedin or topotecan. Future steps may include combination with platinum therapy and a comparison with trabectedin.

NSCLC

Prevalence of ALK-positive NSCLC in Europe

The Lungscape Project is designed to evaluate the expression and clinical significance of ALK in a large cohort of patients with resected NSCLC from 15 European sites (www.etop-eu.org) [Blackhall et al. 2012]. Fiona Blackhall (Christie Hospital NHS Foundation Trust, Manchester, UK) explained that the sites have retrospectively identified cases of NSCLC using clinical demographic and outcome data and available tissue according to predefined protocol criteria. Accepted cases have been assessed for ALK expression using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) was performed on ALK-positive cases and matched ALK-negative controls.

There have been 1099 cases accepted to the database so far and 69 (6.3%) were ALK-positive by IHC. There was a high level of concordance between ALK IHC0+ and FISH+ (90.5% sensitivity and 97.7% specificity between ALK IHC 3+ and ALK FISH+). ALK IHC+ and ALK FISH+ also appeared to provide prognostic information in patients with early-stage, resected adenocarcinoma.

Crizotinib superior to single-agent chemotherapy for ALK-positive advanced NSCLC

Dr Alice Shaw (Massachusetts General Hospital, Boston, MA, USA) presented results of the first phase III study of crizotinib in patients with advanced ALK-positive NSCLC [Shaw et al. 2012]. The global randomized phase III study compared the efficacy and safety of crizotinib with standard chemotherapy (pemetrexed or docetaxel) in 347 patients with ALK-positive, stage IIIB/IV NSCLC who had already been treated with chemotherapy.

Patients randomly received crizotinib (250 mg orally twice daily), pemetrexed (500 mg/m²) or docetaxel (75 mg/m²) intravenously every 3 weeks. ALK was detected by FISH, and patients on docetaxel or pemetrexed with progressive disease were offered crizotinib.

The study showed that crizotinib prolonged PFS (primary endpoint): median 7.7 months versus 3.0 months for patients on chemotherapy (HR 0.49; 95% CI 0.37–0.64; p < 0.0001). The overall response rate (secondary endpoint) was significantly higher for crizotinib versus chemotherapy: 65% versus 20%; p < 0.0001. OS data are still immature and will be reported at a future date; however, 108 patients on chemotherapy crossed over to crizotinib so this will make any OS benefit difficult to ascertain.

The most common treatment-related adverse events with crizotinib were visual disturbance (59% of patients), diarrhoea (53%), nausea (52%), vomiting (44%) and elevated transaminases (36%). Adverse events on chemotherapy included nausea (35%), fatigue (29%), neutropaenia (22%), decreased appetite (21%) and alopecia (20%). The incidence of grade 3/4 treatment-related adverse events was similar between groups (31%). Patients receiving crizotinib reported improved quality of life (QoL) compared with those on chemotherapy.

Dr Shaw concluded by saying that crizotinib is superior to standard single-agent chemotherapy in terms of response, PFS and QoL in ALK-positive patients who have been previously treated with first-line, platinum-based chemotherapy. These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC.

MISSION: third or fourth-line sorafenib does not improve OS but shows relevant antitumour activity

Luis Paz-Ares (Virgen del Rocio University Hospital, Seville, Spain) reported the findings of the phase III Monotherapy Administration of Sorafenib in Patients with Nonsmall Cell Lung Cancer (MISSION) trial, a randomized, double-blind, placebo-controlled study of monotherapy administration of sorafenib in 703 patients with advanced relapsed/refractory NSCLC who were randomly assigned to either oral sorafenib (400 mg twice daily) or placebo [Paz-Ares et al. 2012].

Median OS (primary endpoint) was similar in the two groups (248 versus 253 days); however, median PFS (p < 0.0001), time to disease progression (p < 0.0001), overall response rate (p < 0.001) and disease control rate (p < 0.0001) were significantly greater with sorafenib than placebo. Thus, sorafenib treatment did not meet its primary endpoint of improved survival in this study; however, there is evidence of relevant antitumour activity and further study may show OS benefit in some patient populations.

MISSION posthoc biomarker analysis: patients with EGFR mutant tumours may benefit from sorafenib

To date, there is no specific biomarker that can help select patients for treatment with sorafenib. Tony Mok (Chinese University of Hong Kong, Hong Kong) reported data from an exploratory study that used tumour and/or plasma mutation data from 347 patients who took part in the MISSION trial [Mok et al. 2012]. EGFR and KRAS mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were relatively equal between treatment groups.

Analysis of EGFR-mutation status and effect of treatment on survival showed that patients with EGFR mutations benefited from sorafenib treatment, but those with wild-type EGFR did not (p = 0.023). Median OS was significantly longer in patients with EGFR mutations receiving sorafenib versus placebo (423 versus 197 days; HR 0.48; p = 0.002), but there was no significant difference between sorafenib and placebo in patients with wild-type EGFR. Similar results were seen with sorafenib’s effect on PFS: those with mutated EGFR had better outcomes with sorafenib compared with placebo (HR 0.27; p < 0.001; median PFS 83 versus 42 days) than patients with wild type EGFR (HR 0.62, p < 0.001; median PFS 82 days versus 46 days). However, KRAS-mutation status was not predictive of sorafenib efficacy.

This posthoc analysis suggests that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving third- or fourth-line sorafenib; however, the results are based on a small, nonrepresentative genetic biomarker subpopulation and further prospective investigation is required. The trial however does show that administering new treatments without selecting patients based on potential predictive markers may dilute the real benefit of a targeted agent.

Metastatic melanoma

Combination BRAF and MEK inhibitor therapy delays resistance to treatment with BRAF inhibitors

Published results with BRAF inhibitors showed they could quickly shrink tumours in patients with metastatic melanoma who harboured the BRAF-mutated gene (about half of melanoma patients). However, in many cases, the patients developed resistance to the drugs because of activation of the MAPK pathway. A phase II trial of BRAF and MEK inhibitors in combination (dabrafenib and trametinib, respectively) has been presented by Dr Georgina Long (Melanoma Institute Australia and Westmead Hospital, University of Sydney, Australia) [Long et al. 2012].

There were 162 BRAF V600E mutation-positive and MEK inhibitor treatment-naïve patients (ECOG PS < 2 with RECIST measurable disease) who were randomized to three treatment groups: dabrafenib 150 mg twice daily, dabrafenib 150 mg twice daily plus trametinib 1 mg daily, or dabrafenib 150 mg twice daily plus trametinib 2 mg daily. Crossover from monotherapy to the higher-dose trametinib regimen was allowed after progression. The primary endpoints were PFS, response rate and duration of response with secondary endpoints of OS and safety.

Median PFS was significantly higher in those patients receiving dabrafenib 150 mg plus trametinib 2 mg: 9.4 versus 5.8 months; HR 0.39; 95% CI 0.25–0.62; p < 0.0001 compared with monotherapy), a 60% improvement. The same group comparison also showed the response rate was higher (76% versus 54%, respectively; p = 0.03) as was the median duration of response (10.5 months versus 5.6 months). The 12-month OS was 79% versus 70% despite a crossover of 43% of monotherapy patients to high-dose trametinib therapy and median OS has not been reached. Pyrexia and chills were the most common adverse events leading to dose reduction and interruption in more patients receiving combination therapy than monotherapy. The most common grade 3+ adverse events were in the higher dose group, but there was a lower incidence of hyperproliferative skin lesions compared with the monotherapy group.

Thus, combination therapy with dabrafenib plus trametinib was shown to improve key efficacy endpoints compared with dabrafenib monotherapy among patients with BRAF V600 mutation-positive metastatic melanoma.

Vemurafenib plus the MEK inhibitor, GDC-0973: safety results

Dr Rene Gonzalez (University of Colorado Cancer Center, Denver, CO, USA) presented results of the BRAF inhibitor, vemurafenib, combined with the MEK inhibitor, GDC-0973 in 44 patients (median age 55 years) with unresectable or metastatic melanoma [Gonzalez et al. 2012]. Patients received continuous vemurafenib (720 mg or 960 mg twice daily) and GDC-0973 at one of three doses: 60 mg, 80 mg or 100 mg once daily (14 days on/14 days off, 21 days on/7 days off or continuously. As this was a phase Ib study, the primary endpoints were maximum tolerated dose, dose-limiting toxicity (DLT), safety and pharmacokinetics.

The median number of cycles to date is three with one DLT (grade 3 QT prolongation related to vemurafenib 960 mg leading to its discontinuation) in combination with GDC-0973 60 mg once daily on the 21-days on/7-days off regimen. The most common adverse events across all dose regimens were diarrhoea (54.5%), rash (50.0%), nausea (38.6%), fatigue/asthaenia (34.1%), liver function abnormality (25.0%) and photosensitivity/sunburn (25.0%). The most frequent treatment-related grade ≥3 adverse events were diarrhoea, rash, increased creatine phosphokinase and liver function abnormality, which was seen in 6.8%, 6.8%, 6.8% and 4.5% of patients, respectively. Only one patient developed cutaneous squamous cell carcinoma.

Thus, vemurafenib plus GDC-0973 was tolerable and adverse events were manageable. Early data in eight vemurafenib-naïve patients showed tumour reduction but safety rather than efficacy was the purpose of this study and further research on efficacy is warranted. Two dose levels were selected for phase III investigation: vemurafenib 720 mg and 960 mg twice daily with GDC-0973 60 mg once daily 21 days on/7 days off.

Gastrointestinal cancer

COG gears up for second-line treatment in oesophageal cancer

There are currently no treatments that prolong survival or improve QoL in the substantial number of oesophageal cancer patients who relapse after first-line chemotherapy. Professor David Ferry (New Cross Hospital, Wolverhampton, UK) presented results of the phase III Cancer Oesophagus Gefitinib (COG) study of 450 patients (median age 64 years; PS 0–2) from 51 UK centres [Ferry et al. 2012]. The patients had all relapsed after first-line treatment and were given placebo or the EGFR-inhibitor, gefitinib 500 mg. Primary outcome was OS and secondary outcomes included safety, PFS, health-related QoL (European Organization for Research and treatment of Cancer [EORTC] QLQ-C30 and QLQ-OG25) and predictive biomarkers.

Median PFS was 35 and 49 days for patients who received placebo or gefitinib, respectively (HR 0.795; 95% CI 0.66–0.96; p = 0.017). Median OS was 3.60 months (placebo) and 3.73 months (gefitinib) (HR 0.90; 95% CI 0.74–1.09; p = 0.285). Gefitinib also improved dysphagia and odynophagia (p = 0.004), two important QoL indicators among this patient group.

Although OS was not improved, PFS was, and a durable benefit from gefitinib treatment was also observed in some patients; thus, a translational study (Trans COG) is analysing more than 300 biopsies with the aim of identifying a molecularly defined subgroup where gefitinib treatment is particularly pronounced, for example, are there any activating EGFR mutations that may be the cause of this benefit as is seen in lung cancer?

S-1 plus docetaxel improves survival in advanced gastric cancer

The oral fluoropyrimidine, S-1, is used as a standard treatment for advanced and recurrent gastric cancer in East Asia. An updated analysis of a Japanese phase III START trial of the combination of S-1 with docetaxel was presented by Kazuhiro Yoshida (Gifu University Hospital, Gifu, Japan) [Yoshida et al. 2012].

A total of 639 patients with unresectable or recurrent gastric cancer were enrolled. They were randomly assigned to docetaxel plus S-1 (40 mg/m² docetaxel day 1 intravenous plus 80 mg/m² S-1 days 1–14 orally of a 21-day cycle) or S-1 alone (80 mg/m² S-1 days 1–28 of a 42-day cycle). The primary endpoint was OS and the secondary endpoints included PFS and response rate [Yoshida et al. 2012].

Among the 635 patients analysed, the median survival time was 12.48 months versus 10.78 months in the combination therapy and S-1 groups, respectively (HR 0.837; 95% CI 0.711–0.985; p = 0.0319). PFS was 5.29 months in the combination group and 4.17 months in the S-1 group (p = 0.001). Response rate was 38.8% (32.8–45.2) in the combination group and 26.8% (21.6–32.6) in the S-1 group (p = 0.0048). Neutropaenia was the most frequent adverse event in the docetaxel/S-1 arm with one death occurring from grade 4 thrombocytopenia.

These results pertain to an East Asian population group; thus, further studies would be required in White populations to assess feasibility and tolerance at doses of docetaxel usually used in Europe.

Bevacizumab beyond progression becoming a therapeutic reality

Dr Gianluca Masi (University Hospital of Pisa, Italy) presented data from a randomized phase III trial that evaluated the continuation of bevacizumab beyond progression in patients with metastatic colorectal cancer (mCRC) who had received bevacizumab as part of their first-line therapy [Masi et al. 2012]. There were 185 patients who had progressed following first-line chemotherapy plus bevacizumab and were randomized to receive second-line treatment with chemotherapy alone or in combination with bevacizumab 5 mg/kg every 2 weeks.

OS data are still immature with only 46 and 52 events observed in the combination and chemotherapy-alone arms, respectively. However, the combination of bevacizumab plus chemotherapy improved median PFS (primary endpoint) compared with chemotherapy alone (6.77 months versus 4.97 months; HR 0.65; 95% CI 0.48–0.89; p = 0.0062). This benefit was maintained across various patient subgroups. The safety profile of the combination therapy was consistent with previously reported data.

Accrual to the trial was stopped early based on results from the similarly designed Treatment across Multiple Lines (TML) trial reported in June 2012, which showed that bevacizumab continuation with second-line chemotherapy improved OS significantly in patients with mCRC. This is the second randomized trial investigating bevacizumab continuation beyond first progression and showing that it represents a new treatment option.

Immunomodulation after successful first-line treatment in mCRC

MGN1703 is a synthetic DNA-based immunomodulator with toll-like receptor 9-agonist activity. The phase II/III IMPACT study evaluated the clinical efficacy, immunogenicity and safety of MGN1703 compared with placebo in mCRC patients who achieved complete response, partial response or stable disease following 4.5 to 6 months of first-line standard therapy with FOLFOX/XELOX or FOLFIRI, with or without bevacizumab [Arnold et al. 2012].

Dirk Arnold (University Cancer Centre Hamburg, Hubertus Wald Tumour Centre KMTZ, Hamburg, Germany) stated that randomization following enrolment was halted after interim analysis of unblinded data demonstrated a strong therapeutic effect with MGN1703 (HR 0.53; p = 0.062) in 55 patients comprising the intent- to-treat population [Arnold et al. 2012]. In the per-protocol population, the HR was 0.43 (p = 0.015) in favour of MGN1703. PFS in a predefined target population of 46 patients was 5.8 months versus 2.7 months with MGN1703 and placebo, respectively (HR 0.39; p = 0.013). Following 3 months, 6 months and 9 months of treatment, PFS rates were 43%, 34% and 22%, respectively with MGN1703 and 8%, 8% and 0%, respectively with placebo (p < 0.001).

The treatment was well tolerated with low toxicity. Drug-related adverse events included fever in three patients and one patient each reporting atypical pneumonia, muscle aching, arthralgia, fatigue, paraesthesia, rash, pruritus on injection sites, or increased antinuclear antibodies. A confirmatory clinical study in patients with mCRC is being initiated to investigate further the pronounced PFS observations.

Cetuximab provides no benefit to adjuvant chemotherapy for patients with resected stage III colon cancer

FOLFOX4 (a regimen consisting of oxaliplatin, leucovorin and 5-fluorouracil) is standard adjuvant therapy for resected stage III colon cancer and adding cetuximab to FOLFOX4 has been found to be beneficial among those with metastatic KRAS wild-type colon cancer. Julien Taieb (Georges Pompidou European Hospital, Paris, France) presented preliminary results of the randomized phase III, Pan-European Trials in Alimentary Tract Cancer intergroup (PETACC) PETACC8 trial [Salazar et al. 2012]. In this trial, patients were enrolled regardless of KRAS status initially; Dr Taieb was reporting efficacy and tolerability results in mKRAS patients prior to an amendment restricting enrolment to patients with KRAS wild-type tumours.

There were 1602 patients with KRAS wild-type tumours who were randomized 28–56 days following resection to 12 biweekly cycles of FOLFOX4, with or without weekly cetuximab 250 mg/m² (loading dose 400 mg/m²). The primary endpoint was DFS, and secondary endpoints included OS, treatment compliance, safety and biological studies for the evaluation of markers predictive for relapse and/or treatment efficacy.

Median follow up at this interim analysis was approximately 3.3 years. No difference was seen between the arms for DFS or OS in KRAS wild-type patients or in KRAS/BRAF wild-type patients (n = 984). DFS was worse with cetuximab among patients aged over 70 years of age, in females and in patients with right-sided colon cancer, but a trend towards a better outcome was seen in patients with poor-prognosis tumours (i.e. those with high-grade tumours, T4 disease or perforation/obstruction and was significant in patients with pT4N2 at diagnosis (HR 0.555; 95% CI 0.348–0.885; p = 0.0122).

Thus, there is no benefit in adding cetuximab to FOLFOX4 in patients with resected, stage III, KRAS wild-type or KRAS/BRAF wild-type colon cancer. Dr Taieb suggested that cetuximab may act differently in micrometastatic disease than in stage IV disease. A previous trial, the US N0147 trial (cetuximab plus mFOLFOX6) also failed to show any benefit [Alberts et al. 2012].

EXPAND: no benefit from adding cetuximab to the first-line chemotherapy in advanced gastric cancer

Advanced gastric cancer has a poor prognosis and no established standard treatment. The phase III Erbitux in combination with Xeloda and cisPlatin in AdvaNceD esophagic-gastric cancer (EXPAND) study compared capecitabine and cisplatin with and without cetuximab in patients with gastric and gastroesophageal junction cancer [Lordick et al. 2012]. There were 904 patients across 25 countries enrolled into the study. The primary endpoint was PFS. The study protocol was amended due to the lower PFS observed.

Florian Lordick (Klinikum Braunschweig, Braunschweig, Germany) explained that patient outcome was similar between treatment groups and the primary and secondary endpoints were not met with no significant differences in PFS or OS between the groups. There were more grade 3/4 and serious adverse events with cetuximab but the researchers believe this did not contribute to the negative efficacy result.

Thus, no benefit was seen from adding cetuximab to first-line chemotherapy in advanced gastric cancer. There are questions about whether or not this was the right setting to learn more about anti-EGFR inhibition in this particular cancer. In fact, further analysis of the included patients (e.g. translational research and multivariate analyses testing) may yield beneficial information as well as establish subgroups by genomic expression profiling.

Hypoxic pancreatic tumours seem to be vulnerable to TH-302

TH-302 is a novel anticancer agent that converts under hypoxic conditions to bromo-isophosphoramide mustard, a potent DNA alkylator. Pancreatic cancer is known to be one of the most hypoxic solid tumours. Thus, TH-302 has been investigated in a phase IIb study of 214 previously untreated patients with locally advanced, unresectable or metastatic pancreatic cancer (median age 65 years) [Borad et al. 2012]. Patients randomly received TH-302 240 mg/m² plus gemcitabine, TH-302 340 mg/m² plus gemcitabine or gemcitabine alone (administered on days 1, 8 and 15 of a 28-day cycle). The primary efficacy endpoint was a comparison of PFS between the combination arms and gemcitabine monotherapy.

Mitesh Borad (Mayo Clinic, Scottsdale, AZ, USA) presented results showing that TH-302 improved median PFS: 3.6 months for monotherapy versus 5.5 months and 6.0 months for the lower and higher doses of TH-302 (p = 0.031 and 0.008, respectively). Poorer prognostic factors (older age, poorer PS, reduced albumin) were associated with larger treatment effect. The median OS increased with the addition of the targeted drug, but not significantly: 6.9 months for monotherapy versus 9.2 months and 8.7 months for the lower and higher doses of TH-302.

Skin and mucosal toxicity and myelosuppression were the most common adverse effects attributed to the targeted drug. At the lower dose, rash and stomatitis occurred in 47% and 42% of patients, respectively, but was rarely severe. The higher dose of TH-302 was associated with a greater amount of thrombocytopenia (63%) and neutropaenia (60%) than gemcitabine monotherapy (11% and 31%, respectively).

The trend towards improvement in OS follows the significant improvement in median PFS; however, the study was not designed to detect statistically significant improvements in OS. Also, patients in the monotherapy group were allowed to cross over to receive gemcitabine plus TH-302 upon disease progression, and this may have affected the results. TH-302 340 mg/m² has been selected for future phase III trialling.

Targeted treatments in advanced renal cell carcinoma: latest results

Three phase III trials in advanced renal cell carcinoma (RCC) were presented at the congress. The COMparing the efficacy, sAfety and tolerability of paZopanib versus sunitinib (COMPARZ), INTORACT and INTORSECT trials increase our knowledge about the use of targeted treatment options, in particular temsirolimus, sorafenib, bevacizumab and pazopanib.

COMPARZ: pazopanib similar efficacy to sunitinib in first-line therapy

Dr Robert Motzer (Memorial Sloan Kettering Cancer Center, New York, USA) and colleagues have directly compared the efficacy, safety and QoL for pazopanib and sunitinib in a global phase III trial [Motzer et al. 2012].

There were 1110 treatment-naïve patients with clear cell mRCC and measurable disease in the trial who were randomized to pazopanib (800 mg once daily continuous dosing) or sunitinib (50 mg once daily in 6-week cycles – 4 weeks on/2 weeks off). The primary endpoint was to establish noninferiority of PFS and key secondary endpoints included OS, overall response rate, adverse events and QoL.

The results showed that pazopanib had similar efficacy (was noninferior) to sunitinib in first-line treatment of metastatic RCC. For both drugs, the median PFS by the treating physician’s assessment was slightly more than 10 months.

Both drugs resulted in side effects, but fatigue and skin sores occurred with less frequency for pazopanib than with sunitinib. QoL differences favoured pazopanib in 11 out of 14 domains.

The researchers conclude that pazopanib has similar efficacy to sunitinib but has a differentiated safety and QoL profile.

INTORSECT: temsirolimus is not superior to sorafenib in second-line treatment

Results of the first head-to-head phase III trial comparing the VEGF inhibitor, sorafenib, with the mammalian target of rapamycin inhibitor, temsirolimus, in RCC were reported by Thomas Hutson (Baylor Sammons Cancer Center, TX, USA) [Hutson et al. 2012]. There were 511 RCC patients (median age 60 years; 83% clear cell histology) from 112 sites in the trial, whose disease had progressed after first-line sunitinib therapy (ECOG PS 0 or 1).

A total of 389 patients were assessed for final analysis. There were no significant differences in median PFS (primary endpoint) with temsirolimus (4.28 months) and sorafenib (3.91 months), nor any significant difference in OS (secondary endpoint): temsirolimus was 12.27 months compared with 16.64 months for sorafenib. Based on these results, the researchers stated that temsirolimus did not show superiority to sorafenib in PFS or OS.

INTORACT: bevacizumab plus temsirolimus offers no advantage over bevacizumab plus interferon

Bevacizumab and temsirolimus target different molecular pathways in RCC so their combined use was worthy of clinical investigation. Brian Rini (Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA) presented results of the INTORACT trial, a global phase IIIb study comparing temsirolimus plus bevacizumab with interferon plus bevacizumab as first-line treatment in predominantly clear cell metastatic RCC [Rini et al. 2012]. There were 791 patients (mean age 58 years) enrolled in the study who received temsirolimus (25 mg intravenously weekly) plus bevacizumab (10 mg/kg intravenous every 2 weeks), or interferon (9 MU subcutaneously three times weekly) plus bevacizumab (10 mg/kg intravenous every 2 weeks). Dose reductions were allowed for temsirolimus and interferon, but not for bevacizumab.

At the data cutoff for final analysis, 489 patients had independently assessed PFS events. Median PFS with the temsirolimus combination was 9.1 months, compared with 9.3 months in the interferon group. Median OS was 25.8 months in the temsirolimus group and 25.5 months for the interferon group.

Thus, the study failed to find an advantage for bevacizumab plus temsirolimus over bevacizumab plus interferon.

Footnotes

Acknowledgements

This report was compiled following attendance at the 2012 European Society of Medical Oncology Congress in Vienna (28 September–2 October). It was compiled from attendance at presentations and press conferences and includes material presented therein and/or in the programme abstract as well as from session discussions. Our aim has been to collate the key studies in medical oncology as a starting point for further reading. Fuller descriptions of study methodologies, limitations and results are given in the full abstracts, which have been published in Ann Oncol (2012) 23 (Suppl 9): ix 21–ix 602 and the ESMO 2012 Late-breaking, press and deferred publications abstracts in Ann Oncol (2012): doi:10.1093/annonc/mds499, ixe 1–ixe 30.

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Targeted therapies in medical oncology: successes,failures and next steps