ASCO 2018 Review
HR+/HER2- Therapies Take The Stage: With ASCO 2018 now behind us, we have time to reflect on the advances and challenges that remain for patients with metastatic breast cancer (mBCa). Hormone receptor positive (HR+) (mBCa) was a key focus area for this year’s meeting. Key takeaways and analysis of selected HR+ mBCa data are presented below:
KEY TAKEAWAYS in HR+/HER2- Breast Cancer
1) The vast majority of patients are receiving Cdk4/6 inhibitors in first line (1L) in combination with endocrine therapy. Despite its near-ubiquitous use, many patients require active monitoring due to Cdk4/6 side effects and/or are too old or frail to take Cdk4/6 in the first place.
2) Oncologists’ views are mixed regards to second line (2L) treatments and beyond.
3) With a lack of data to support switching from on Cdk4/6 to another after progression in 1L, or to remaining on the same Cdk4/6 inhibitor, oncologists are unsure if there is a benefit to prescribing them in 2L.
4) Many oncologists are prescribing fulvestrant in 2L. Due to a lack of randomized data, it is estimated that Fulvestrant has ~4 month PFS, ~10% ORR, and ~25% CBR in this treatment line (extrapolated from FALCON and BOLERO-2 trials).,
5) There is an unmet need for agents that can improve upon fulvestrant activity in patients who have progressed on anti-estrogen and anti-Cdk4/6 therapy.
6) Given the lack of treatment options in 2L, everolimus is now being used by a small minority clinicians with or without exemastane, despite concerns about drug-induced irreversible pneumonitis. Previously, everolimus had largely been relegated to 3L+.
7) Data presented from emerging 2L treatments, including PI3K (SANDPIPER trial) and PD-L1 (abemaciclib combination), was underwhelming. Upon data release, Roche announced that it terminated development of their PI3K inhibitor, taselisib, in HR+ breast cancer based on modest efficacy and poor tolerability. Other PI3K inhibitors still in development will hopefully provide better efficacy and tolerability.
8) For later line, hormone-refractory patients, antibody-drug conjugates (TROP2 and HER3-targeted ADCs) generate positive efficacy data.
UNMET NEED: Cdk 4/6 inhibitors in combination with an antiestrogen is the dominant treatment in 1L HR+/HER2- mBCa. Some patients, mainly those with less aggressive disease receive antiestrogen monotherapy in 1L; the vast majority of patients receive combination therapy with a Cdk4/6 inhibitor. Even though Cdk4/6 are approved in 2L, perceived cross-resistance across Cdk4/6 limits clinical interest in swapping Cdk4/6 across treatment lines. Given the broad use of antiestrogen in combination with anti-Cdk4/6 in 1L, there is now a significant unmet need for therapeutics that can address the resistance profile generated by the combination of these agents. Currently, there is no randomized data indicating how therapies perform after Cdk4/6. Many clinicians are using fulvestrant post-Cdk4/6 but they are looking for an agent that will extend PFS further than fulvestrant alone, and with a tolerable safety profile. Beyond fulvestrant, the data are not encouraging for the combination of everolimus and exemestane. Data at ASCO were presented from a retrospective subpopulation analysis from the BOLERO-2 trial, indicating that everolimus + exemestane (n=26) generated PFS of 4.4 months.
COMPRESSION OF 1L and 2L: Given the broad use of anti-Cdk4/6 in 1L and the lack of therapeutic options available to treat anti-Cdk4/6 resistance in 2L, we are going to see a divergence in development strategy, costs, and timelines over the next few years. In 1L, new therapies may be additive (a triplet) to antiestrogen + anti-Cdk or may be a two-drug combination agent that generates greater efficacy than the current anti-Cdk4/6 combinations (MONALEESA-3 data presented at ASCO). In 2L, there is a need for better efficacy and tolerability, and a strong interest to enroll patients in clinical trials. The benchmark in 2L is likely to a comparison of fulvestrant monotherapy.
SANDPIPER: In a Phase 3 study comparing fulvestrant +/- PI3K (taselisib) in antiestrogen resistant patients, taselisib (Roche) generated a 2-month improvement in PFS (6.5 months) but 17% of patients (vs 2% in Fulvestrant arm) discontinued treatment. Given the modest clinical benefit relative to additive toxicity and the emergence of Cdk4/6 as a superior alternative, Roche terminated development of taselisib in HR+ breast cancer.
PD-L1: The addition of pembrolizumab to abemaciclib in 2L/3L recurrent mBCa was moderately beneficial as 16-week ORR improved from 6.8% to 14.3% when compared to MONARCH-1 study that evaluated Abe monotherapy. Interestingly, the number of patients with stable disease (~60%) was almost identical between treatment groups. This data would suggest that PD-L1 was mildly additive. A trial is planned to evaluate a triplet, pembrolizumab + abemaciclib + anastrazole, in 1L.
SACITUZUMAB GOVITECAN: For later-line, hormone-refractory patients who require novel chemotherapy or chemotherapy-like treatments, ADCs present an intriguing option. Sactizumab govitecan is antibody drug conjugate (ADC) targeting the TROP2 receptor with an irinotecan payload that was evaluated in 54 heavily pre-treated HR+ mBCa patients.  Interim data is quite promising with 31% ORR, 48% CBR, and a median duration of response of 7.4 months. In the subgroup of those who previously received Cdk4/6 inhibitors (n=37), ORR was 24%, CBR was 48% and median PFS was 6.8 months. Compared to irinotecan chemotherapy, the drug appears to be better tolerated, with only 2 patients discontinuing treatment due to possibly-drug related toxicity. The only grade 3 or 4 AE’s were neutropenia (42%), while previous studies noted that 36% of patients experienced alopecia.
U3-1401: Preliminary data from the dose escalation of this HER3-targeted ADC that carries a novel topoisomerase I inhibitor payload in heavily pre-treated patients was presented. HER3 is enriched in ~25% of EH+/HER2- breast cancers. Similar to sactizumab govitecan, U3-1401 generated solid responses in patients; however, the ADC had a strong impact on blood counts and liver function that led to multiple dose-limiting toxicities.
BOLERO-6: This Phase 2 study evaluated everolimus +/- exemestane in 2L patients who had progressed on anastrazole or letrozole. Everolimus monotherapy patients lived almost 33% longer than combination patients despite having a lower mPFS (6.5 vs 8.4 months) than the combo. ORR and CBR rates were not disclosed.
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