Highlights from ASCO

The 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) was held from 29th May to 2nd June, in Orlando, FL. Whilst a previous editorial published in Cancer Drug News (see Issue No. 364 - "Looking ahead to ASCO") noted that the 4,000 study abstracts for this year's meeting had drawn a mainly disappointing response, there were numerous encouraging results reported. Of particular note were positive Phase III data with Roche's Herceptin (trastuzumab) in aggressive gastric cancer (GC), Phase II results with AstraZeneca's olaparib in breast (BC) and ovarian cancer (OC), and final results from a Phase II trial of OncoGenex Pharmaceuticals' OGX-011 in prostate cancer (PCA).

Specifically, trastuzumab showed unprecedented survival in aggressive GC. Data from the international, Phase III ToGA study demonstrated that adding the drug to standard chemotherapy increases average survival by 26 per cent in patients with HER2-positive advanced and inoperable GC compared to chemotherapy alone. This combination is also particularly beneficial to GC patients whose tumours express higher levels of HER2, increasing their median survival to 16 months. Trastuzumab is already well established as the foundation of care for patients with HER2-positive BC and now, based on the ToGA results, Roche is to seek regulatory approvals for its use in HER2-positive advanced GC.

Separately, olaparib showed potential to make significant impact on outcomes of patients with BRCA-deficient BC and OC. Phase II data for the novel, oral poly (ADP-ribose) polymerase (PARP) inhibitor demonstrated that it is effective and well tolerated in women carrying the BRCA1 or BRCA2 gene mutation with BC or advanced OC. PARP inhibition is being explored as a new therapeutic approach in cancers with impaired DNA repair pathways, one example of which is cancers with BRCA deficiency. Indeed, both studies were selected for inclusion in the 'Best of ASCO' scientific programme.

Finally, it was reported that OGX-011 provides survival benefit to PCA patients. OncoGenex presented final results from a Phase II trial, with analyses indicating a survival benefit in PCA patients treated with the compound in combination with docetaxel compared to docetaxel alone. Patients treated with OGX-011 had a rate of death 51 per cent lower than those treated with docetaxel alone. Scott Cormack, President and CEO of OncoGenex, noted that a 39 per cent reduction in death, consistent with the previously-disclosed preliminary analysis, would be a significant advancement for treatment in this patient population, adding: "the multivariate analysis shows an even greater reduction in death rate than our preliminary data and increases our confidence that we are seeing a real and meaningful survival benefit for patients treated with OGX-011...these data clearly justify advancing to Phase III development, and we expect these data will be key in our partnering discussions for future clinical development and potential commercialisation."

Alice Rossiter - Cancer Drug News Editor

Targeted combination effective against metastatic BC

GlaxoSmithKline has reported positive data from the first randomised, multi-centre, open-label Phase III trial of the combination of two targeted agents, Tykerb (known as Tyverb in Europe; lapatinib) and Herceptin (trastuzumab), in women with HER2-positive metastatic breast cancer (BC).

In the study, 296 patients with HER2 (ErbB2)-positive BC who had documented progression on trastuzumab treatment in the metastatic setting were eligible to be randomised to receive lapatinib (1,000mg) plus trastuzumab (2mg/kg weekly after 4mg/kg loading dose) or lapatinib alone (1,500mg). Patients were heavily pretreated and had received a median of six prior anticancer regimens. Patients had received a median of three prior lines of trastuzumab. The primary endpoint of the study was progression-free survival (PFS), and secondary endpoints included clinical benefit rate, response rate and overall survival. If patients progressed on the lapatinib monotherapy arm after four weeks of therapy, they could cross over to receive the combination of lapatinib+trastuzumab.

Despite receiving multiple prior lines of anticancer therapy, patients who received lapatinib plus trastuzumab in this study experienced:

• a statistically significant increase in median PFS versus lapatinib alone (12 vs 8.1 weeks);
  a 27 per cent reduction in the risk of disease progression (hazard ratio [HR]=0.73; p=0.008);
• a response rate of 10.3 versus 6.9 per cent;
  double the overall clinical benefit rate versus lapatinib alone (24.7 vs 12.4 per cent; p=0.01); and
• a trend in improved overall survival (HR=0.75; p=0.106).
  The study also demonstrated the activity of lapatinib as a single agent in this patient population, with patients on this arm achieving a median PFS of 8.1 weeks and an overall clinical benefit rate of 12.4 per cent.

Adverse events were similar in both arms, with Grade 1/2 diarrhoea significantly higher in the lapatinib+trastuzumab arm (53 vs 41 per cent; p=0.03). Two patients in the combination arm and one patient in the lapatinib monotherapy arm experienced symptomatic decreases in left ventricle ejection fracture (LVEF); one patient in the lapatinib+trastuzumab arm died due to a pulmonary thromboembolism with progressive malignant pleural effusions; two patients with LVEF decrease later recovered. Isolated cases of asymptomatic transient decreases in LVEF were noted in both treatment arms.

Both treatments target the HER2 protein but work in different ways. Trastuzumab attaches to the outside of the HER2 protein, while lapatinib enters the cell to block signals from the HER2 protein for the cancer to grow. The clinical synergy of lapatinib and trastuzumab confirms previous observational findings in preclinical studies and previously reported data from a Phase I study. These latest findings confirm the rationale for further research of this combination in earlier lines of therapy in the metastatic setting and in early-stage disease. Additional analysis is under way to explore the benefit that lapatinib plus trastuzumab can offer to less heavily-pretreated patients.

Matthew Dennis - Editor, Cancer Drug News