Overcoming Resistance in Breast Cancer: Is there a role for mTOR inhibition in HER2+ disease?
| Jun 2, 2013
Co-authored by Stephanie Hawthorne, PhD, Director
Activation of the PI3K-AKT-mTOR pathway has been implicated as one of several potential mechanisms for acquired resistance to HER2-targeted and hormone therapy in breast cancer. Preclinical and clinical results support investigation into whether acquired resistance can be overcome by downstream inhibition of this pathway. A number of agents currently in clinical development target different kinases in the pathway, the most advanced of which are the mTOR inhibitors ― Afinitor® (everolimus, Novartis) and Torisel® (temsirolimus, Pfizer), both approved for various cancer indications. Within breast cancer, Afinitor in combination with Aromasin® (exemestane, Pfizer) was approved by the U.S. FDA and the European Medicines Agency (EMA) in July 2012 for the treatment of HR+ metastatic breast cancer (mBC), in patients who have failed a prior aromatase inhibitor. This approval was based on a 6.9 month improvement in progression-free survival (PFS) and a trend to overall survival (OS) benefit at the interim analysis (HR 0.77)1. Having clearly demonstrated the role of mTOR inhibition in overcoming resistance to hormone therapy, the natural question is whether this approach is clinically effective in patients resistant to HER2-targeted therapy.
To address this question, Novartis initiated the Phase III BOLERO-3 trial (NCT01007942) which compared Herceptin® (trastuzumab, Genentech/Roche) plus vinorelbine with or without Afinitor in 569 locally advanced or metastatic breast cancer patients who had received a prior taxane and who were resistant to Herceptin. Notably, resistance was defined as either progression while on or within 12 months of adjuvant Herceptin or progression within 4 weeks of Herceptin for metastatic disease. The first results of this trial were reported on June 2 at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in the oral session for HER2/ER Breast Cancer2. Ultimately, 16% of patients were enrolled in the first-line setting, 42% were enrolled as second-line, and 27% had received prior Tykerb® (lapatinib, GlaxoSmithKline). The addition of Afinitor significantly improved PFS (the primary endpoint) by local assessment by 1.2 months (7.0 months versus 5.8 months, HR 0.78, p=0.0067). There was no significant difference in any of the reported secondary endpoints for the Afinitor and placebo arms: objective response rate (ORR: 40.8% versus 37.2%, p=0.2108), quality of life (time to definitive deterioration of global health status QL2 score: 8.3 months versus 7.3 months, HR 0.98, p=0.8386), and overall survival (at interim analysis based on 220 of 384 events: 36.3% versus 41.1% deaths; statistics not provided), respectively. Subgroup analyses suggest that the Afinitor benefit was similar regardless of performance status or prior Tykerb exposure, but differential benefits were observed in a few patient subgroups ― patients who received prior neo/adjuvant Herceptin derived greater benefit with Afinitor than those who had not (HR 0.65 versus 0.92), as did patients who were ER-/PR- compared to those who were ER+ and/or PR+ (HR 0.65 versus 0.93), and those who were younger (<65 years HR 0.77 versus ≥65 years HR 0.93).
In terms of safety, the toxicity profile was similar to that reported with Afinitor in other studies, namely higher rates of Grade 3/4 stomatitis, fatigue, hyperglycemia, anemia, and febrile neutropenia. The adverse event profile and the need for dose reductions lead to a decreased dose intensity for Afinitor compared to placebo (77% versus 96% of planned dose intensity; vinorelbine dose intensity was reduced in both arms and not statistically different (64% versus 73%, respectively).
These results are somewhat disappointing. The magnitude of PFS benefit with Afinitor was modest in the intent to treat population (1.2 month difference at the median and a 22% reduction in the risk of progression or death). While statistically significant, the clinical meaningfulness of this benefit is questionable. With regard to the PFS analysis, only investigator-assessed outcomes were reported. An independent central review analysis would be ideal to have since typically the level of benefit varies between investigator and central review analysis; such an analysis is likely underway. The OS analysis is premature, and a Kaplan-Meier curve or any statistical analyses were not presented. Although there is a numerical 4.8% reduction in the number of deaths in favor of the Afinitor arm, the available data is too limited to allow us to make any prediction as to whether the OS data will eventually prove to be significant or not. The final OS data is expected in 2014.
There is a precedent for approval in relapsed breast cancer with a PFS benefit without OS benefit ― Tykerb was approved based on a 4.3 month PFS benefit but no difference in OS3 ― although more recently Kadycla® (ado-trastuzumab, Genentech/Roche) was approved based on a significant improvement in both PFS and OS compared to Tykerb/capecitabine4. Whether or not the data presented on June 2 for Afinitor would support regulatory approval is therefore questionable.
The treatment of HER2+ breast cancer has exploded in the last year, expanding from having just two options ― Herceptin and Tykerb ― to now having four, following the approval of Perjeta® (pertuzumab, Genentech/Roche) by the FDA in June 2012 and the EMA in March 2013, and the approval of Kadcyla by the FDA in February 2013 (European approval still pending). Physicians are just starting to develop their paradigms to incorporate all of these agents into treatment, although the National Comprehensive Cancer Network (NCCN) recommends first-line treatment with Herceptin plus Perjeta and docetaxel followed by Kadcyla in second-line for patients with HER2+ mBC, with other options (such as Tykerb plus capecitabine or Herceptin re-treatment) for later lines5. If approved, where will Afinitor fit into this treatment paradigm? If we compare the outcomes from BOLERO-3 with those from other trials in the Herceptin-pretreated setting (see Table 2), the data suggests that Afinitor may provide a weaker level of benefit than Kadcyla or Tykerb/capecitabine. It’s likely that any role for Afinitor will be limited to third-line or even later, especially since Afinitor proved effective in patients treated with prior Tykerb. Additionally, the suggestion that all clinical benefit with Afinitor was limited to those patients who were ER-/PR- could further limit its utilization to the less than half of HER2+ patients who are ER-/PR-.
Other questions remain. Which dose of Afinitor should be used in breast cancer? The BOLERO-3 trial utilized a 5 mg/day dose, whereas in the BOLERO-2 trial in combination with Aromasin and in the ongoing BOLERO-1 trial in first-line HER2+ mBC Afinitor is given at a dose of 10 mg/day. With the reduced dose intensity observed in BOLERO-3 it seems unlikely that a higher dose should be used, but are there implications for the ongoing BOLERO-1 trial? Should Afinitor be restricted to the subpopulations that derived the greatest benefit (or conversely, not be used in those subgroups who derived no benefit)? Do the data from BOLERO-3 foreshadow outcomes in the ongoing BOLERO-1 trial (NCT00876395), which will compare Herceptin/paclitaxel with or without Afinitor in first-line HER2+ mBC; results are expected later this year.
- Afinitor prescribing information, accessed June 2, 2013.
- O’Regan et al, Abstract 505, ASCO 2013
- Geyer et al, NEJM, 355(26): 2733-2743, 2006.
- Kadcyla prescribing information, accessed June 2, 2013.
- National Comprehensive Cancer Network guidelines, Breast Cancer, version 3.2013.
- Tykerb prescribing information, accessed June 2, 2013.