36th ESMO Congress report: practice changing studies and personalized treatment

Published in: Volume 6 / Year 2012 / Issue 3-4
Category: Conference Report
Page: 34-36
Visits: 1531 total, 1 today

Abstract:
The 37th Congress of the European Society for Medical Oncology (ESMO) held 28 September to 2 October 2012 in Vienna, Austria, was a record breaker on all levels. With 16,394 participants including 1,116 from the US, 539 from Japan, 292 from China and 550 from Argentina and Brazil.

The strong scientific programme benefitted from the submission of 2,200 abstracts – an increase of more than 30% since the previous ESMO Congress in 2010 – of which 1,239 were presented. There were over 50 late breaking abstracts submitted and data from 110 phase III trials were reported. The five-day event was comprised of two Presidential Symposia, several Joint Symposia with other professional and scientific societies, several special sessions, proffered paper sessions, and seven Young Oncologist sessions, together with 37 industry sponsored symposia.

A primary emphasis was placed on personalized medicine and how it will change the future landscape in oncology.

The key message delivered by Dr Josep Tabernero, Chair of the ESMO 2012 Scientific Committee was that personalized cancer medicine is becoming a reality in clinical work. Many of the presentations contained new information on biomarkers and several studies that used biomarker data to stratify patient treatment. Some of the results presented were practice changing and many others suggested new or alternative treatment options for patients.

The ESMO Scientific Committee has turned a watchful eye to the economic crisis and included topics such as the economic burden, both direct and indirect, of cancer in Europe, health economics, drug costs and the unsustainability of cancer care, which were presented and discussed by experts.

This report is an overview of representative scientific presentations made during the congress by premier international investigators. It attempts to represent the diversity and depth of the ESMO 2012 scientific programme.

Crizotinib superior to standard chemotherapy in patients with advanced ALK-positive non-small cell lung cancer

A randomized phase III study (PROFILE 1007) compared the efficacy and safety of crizotinib to standard chemotherapy with pemetrexed or docetaxel as second-line treatment for patients with advanced FISH-determined ALK positive non-small cell lung cancer (NSCLC). Over a two-year period, the study enrolled 347 patients with stage IIIB/IV, ALK+ NSCLC who had previously received one platinum-based regimen; 173 patients were randomized to crizotinib and 174 to either pemetrexed (58%) or docetaxel (42%). Patients who progressed on pemetrexed or docetaxel were offered crizotinib. The trial’s primary endpoint was progression-free survival (PFS) per independent radiologic review, with secondary endpoints of objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes. The study met the primary endpoint by showing crizotinib superiority over pemetrexed or docetaxel with a median PFS 7.7 months compared with 3.0 months (p < 0.0001). Patients treated with crizotinib also had a significantly higher ORR of 65.3% compared with 19.5% (p < 0.0001). An interim analysis of OS done at 28% events showed no statistically significant difference between crizotinib and pemetrexed or docetaxel. More patients receiving crizotinib over chemotherapy reported improvement in symptoms from baseline of cough, dyspnoea, fatigue, alopecia, insomnia and pain, p < 0.0001. Improved global quality of life also favoured crizotinib, p < 0.0001. The most common treatment-related adverse events with crizotinib were vision disorder, which was reported by 60% of patients; 60% of patients reported diarrhoea, 55% had nausea, 47% vomiting and 36% of patients reported elevated transaminases. Adverse events including nausea, constipation, fatigue and rash were reported by 37%, 23%, 33%, 21%, respectively, and 17% of patients receiving pemetrexed or docetaxel (Shaw et al. Abstract # LBA1_PR).

Practice point and future research opportunities
Crizotinib may be considered the standard of care for second-line treatment of patients with previously treated advanced ALK positive NSCLC. Results from this study showed significantly improved progression-free survival, response rate and quality of life with crizotinib over pemetrexed or docetaxel. Lack of a difference in OS rates was most likely due to the immaturity of data at the interim analysis and to the large number of patients who crossed over to treatment with crizotinib.

A head-to-head comparison of pazopanib versus sunitinib as first-line treatment of patients with metastatic renal cell carcinoma

The randomized, open label, phase III COMPARZ (COMParing the efficacy, sAfety and toleRability of paZopanib versus sunitinib) trial was a head-to-head comparison of the efficacy, safety and tolerability of pazopanib versus sunitinib in 1,110 treatment naive patients with clear cell metastatic renal cell carcinoma and measurable disease. The patients were randomized 1:1 to receive either continuous pazopanib or sunitinib in 6-week cycles. The primary endpoint was PFS and key secondary endpoints included OS, ORR, adverse events, and quality of life. Patient characteristics were balanced between arms. The non-inferiority of pazopanib was demonstrated; the upper bound of the 95% confidence interval for PFS was less than 1.25. In 557 pazopanib treated patients versus 553 receiving sunitinib, the independent review committee and investigator determined median PFS rates were 8.4 vs 9.5 months, hazard ratio (HR) 1.0466 and 10.5 vs 10.2 months, HR 0.998, respectively. Median OS was 28.4 months with pazopanib and 29.3 with sunitinib, HR 0.93. The ORR favoured pazopanib at 31% compared with 25% in the sunitinib arm. The most commonly reported adverse events—reported by 40% or more patients—of diarrhoea, fatigue, hypertension and nausea occurred at similar frequency in both treatment arms. Hand–foot syndrome was reported by 29% of pazopanib and 50% of sunitinib patients; higher rates of dysgeusia, dyspepsia, hypothyroidism, mucositis, thrombocytopenia and neutropenia were also seen in the sunitinib arm. More patients in the pazopanib arm showed liver function adverse events; 33 vs 18 showed elevated ALT (HR 1.74) and 31 vs 25 showed elevated AST (HR 1.49) than with sunitinib. Differences in 11 of 14 quality of life domains, all favouring pazopanib, were reported but the minimally important difference was not met (Motzer et al. Abstract # LBA8_PR).

Practice point and future research opportunities
Pazopanib demonstrated non-inferiority to sunitinib as first-line treatment of patients with clear cell metastatic renal cell carcinoma with a more favourable safety profile and improved patient reported quality of life domains.

Continuation of bevacizumab beyond progression improves survival in patients with metastatic colorectal cancer

A phase III study conducted by Gruppo Oncologico Nord Ovest (Italy) evaluated whether continuing bevacizumab with second-line chemotherapy beyond progression would improve survival in patients with unresectable metastatic colorectal cancer, as suggested by retrospective data. The trial randomized patients with metastatic colorectal cancer who had received bevacizumab plus first-line chemotherapy with fluoropyrimidine, FOLFIRI, FOLFOX or FOLFOXIRI to receive a second-line chemotherapy using either FOLFOX or FOLFIRI alone (arm A) or together with bevacizumab (arm B). Patients were stratified according to centre, performance status (PS 0 vs 1–2), disease-free interval from the last administration of first-line chemotherapy (≤ 3 months vs > 3 months) and the second-line regimen. The primary endpoint was PFS. The trial was designed to randomize 262 patients but accrual was halted on 11 May 2012 when it was noted that the similarly designed AIO/AMG ML18147 trial showed improved OS with bevacizumab beyond progression. Prior to the early end, the trial had randomized 185 patients; 184 patients were included in the intent-to-treat analysis. Arm A comprised 92 patients who were 75% male with a median age of 66 years; 82% of patients had PS 0 and 76% had disease at multiple sites; liver only disease was seen in 15% of patients. Patients in arm B were slightly younger with a median age of 62 but other characteristics were the same or similar to arm A. The study met the primary endpoint; at median follow up of 18 months there were 172 (93%) events for PFS and median PFS was 4.97 months for arm A chemotherapy alone patients compared to 6.77 months for arm B, chemotherapy plus bevacizumab patients, hazard ratio (HR) 0.65, p = 0.0062. A PFS analysis that adjusted for stratification factors, age and sex confirmed that bevacizumab added to chemotherapy improved PFS over chemotherapy alone, HR 0.70, p = 0.032. An increased response was also demonstrated in arm B with response rates of 18% for chemotherapy alone and 21% for chemotherapy plus bevacizumab, but the difference was not statistically significant. Overall survival data are not yet mature with arm A having 52 events and arm B having 46 events thus far. The adverse event profile was consistent with previously reported data for bevacizumab plus chemotherapy (Masi et al. Abstract # LBA17).

Practice point and future research opportunities
This is the second randomized, controlled trial to show continued bevacizumab plus second-line chemotherapy after progression improves progression-free survival in patients with metastatic colorectal cancer and may represent a new treatment option.

One year of adjuvant trastuzumab remains the standard of care for patients with HER2-positive early breast cancer

HERA was an international, multi-centre, phase III randomized trial that evaluated whether longer-term trastuzumab treatment would improve outcome of patients with HER2-positive early breast cancer. A total of 5,102 women were randomized, following completion of primary therapy consisting of surgery, chemotherapy and radiotherapy, as indicated, to observation only or trastuzumab every 3 weeks for 1 year or 2 years. The efficacy analysis compared the outcome of 1,703 women receiving trastuzumab for 1 year and 1,701 women receiving trastuzumab for 2 years who were disease-free at 1 year post-randomization. The primary endpoint was disease-free survival (DFS) and secondary endpoints included OS and time to distant recurrence. At 8 years of follow-up, DFS and OS in the two arms were comparable, with no significant difference between treatment duration; however, trastuzumab treatment for either 1 or 2 years showed a significant benefit compared to observation, despite selective crossover. The primary cardiac endpoint (cardiac death or severe congestive heart failure defined as a NYHA class III or IV, confirmed by a cardiologist, and a significant left ventricular ejection fraction – LVEF decrease) was comparable at 0.96% vs 0.83% but the secondary cardiac endpoint (defines as an absolute decline ≥ 10% points from baseline LVEF and to < 50%) was 7.17% vs 4.10% for the 2 year and 1 year arms, respectively (Goldhirsch et al. Abstract # LBA6_PR).

Results from the recent FinHer study showed a similar magnitude of benefit obtained with 9 weeks of adjuvant trastuzumab as with 1-year treatment. Concerns of over-treatment and cardiac toxicity associated with trastuzumab led the French National Cancer Institute to initiate an academic, randomized, non-inferiority comparison of trastuzumab exposure of 6 months to the standard 12-month course. The PHARE (Protocol for Herceptin as Adjuvant therapy with Reduced Exposure) trial enrolled 3,382 patients with HER2-positive early breast cancer who had previously received at least 4 cycles of (neo)-adjuvant chemotherapy. The patients were randomized 1:1 using a minimization algorithm stratified by concomitant or sequential trastuzumab administration with chemotherapy, oestrogen receptor status and centre to receive trastuzumab for 6 or 12 months. The primary endpoint was DFS, and OS and cardiac toxicity were investigated as secondary aims. Disease and treatment characteristics were well-balanced between the arms. Patients had a median age of 55 years, median tumour size of 20 mm, node involvement was seen in 45% of patients, 56% of patients had Scarff-Bloom-Richardson grade III disease and 58% were ER-positive. In all, 88%, 58% and 73% of patients had received prior radiotherapy, concomitant trastuzumab administration and anthracycline and taxane containing chemotherapy, respectively. The median follow-up was 47.2 months. No significant difference was shown in DFS between 6 and 12 months of treatment, the hazard ratio was 1.28 (p = 0.29) (Pivot et al. Abstract # LBA5_PR).

Practice point and future research opportunities
One year of adjuvant trastuzumab remains the standard of adjuvant care for patients with HER2-positive early breast cancer. The response is durable and the incidence of cardiac events remained low at a median follow-up of 8 years in the HERA study. Non-inferiority of a 6-month regimen could not be demonstrated in the PHARE study.

Author

Svetlana Jezdic, MD
European Society for Medical Oncology
4 Via L Taddei
CH-6962 Viganello-Lugano, Switzerland

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