FirstWord Executive Editor Simon King rounds up five key takeaways from this weekend's presentations at the ESMO 2018 Congress. Keep an eye out for more in-depth analysis from the meeting over the next few days.
Landmark data for PARP inhibition
PARP inhibitors have emerged as an important new drug class over the past few years, predominantly in ovarian cancer where they are used to treat recurrent disease.
Stunning data from the SOLO-1 trial for AstraZeneca and Merck & Co.'s Lynparza now promises to radically change the treatment landscape for BRCA mutation patients (approximately 15 percent of all ovarian cancer cases) in the first-line setting, showing a 70-percent reduction in the risk of disease progression or death versus the current standard practice of waiting for disease recurrence.
These results offer the increased potential of cure for some patients given the magnitude of demonstrated effect following just two years of Lynparza treatment subsequent to chemotherapy in the first-line maintenance setting.
The data are also likely to grow enthusiasm around the class (and broader approaches to DNA damage repair) and prompt further research efforts to broaden the applicability of PARP inhibition by tumour type.
Lynparza - and more recently Pfizer’s Talzenna - have both been approved for the treatment of BRCA mutated, HER2-negative breast cancer, while Clovis Oncology presented promising (and what it hopes to be registration-supporting) data for its PARP inhibitor Rubraca in BRCA-positive prostate cancer here in Munich this weekend.
A first-step for immunotherapy in breast cancer
Immunotherapy has finally made a definitive mark for the treatment of breast cancer; specifically in patients with triple negative disease - which accounts for around 15 percent of all breast cancers - and whose tumours express the PD-L1 biomarker.
In this cohort, the combination of Roche's PD-L1 inhibitor Tecentriq with chemotherapy was shown to significantly improve progression-free survival (PFS) to 7.5 months from 5 months with chemotherapy alone. This was described as a clinically meaningful benefit enhanced by an impressive hazard ratio of 0.61, which was also replicated at an interim analysis for overall survival (OS). Though not formally tested due to the hierarchical statistical design of Roche's study, this interim analysis showed a median OS benefit of around 10 months in PD-L1 positive patients.
Until fairly recently (Roche guided heavily towards a PD-L1 only benefit in its third-quarter results last week), analysts had been expectant of broader efficacy for the combination, so there will likely be some disappointment from the financial community.
Questions were raised, however, as to whether use of different chemotherapy regimens could extend clinical benefit to PD-L1 negative patients or whether future study designs can be modified to further enrich the target population for breast cancer immunotherapy; perhaps focusing on those patients with higher rates of PD-L1 expression where the need to use chemotherapy could be eliminated altogether.
As targeted breast cancer therapies become more personalised
While there will be some disappointment that Roche's combination did not benefit a broader patient group (PD-L1 positives account for around 40 percent of all triple negative breast cancer patients the company estimates) a key theme at this year's meeting is the increased focus on genomic profiling of breast cancer patients to aid development of personalised therapeutics.
Novartis' SOLAR-1 trial, studying the PI3K inhibitor alpelisib in women harbouring a PIK3CA mutation (which account for around 40 percent of all hormone receptor-positive, HER2-negative breast cancer patients), should therefore be regarded as an important step in this direction; particularly as the tolerability of less specific PI3K inhibitors has proven prohibitive of durable use for this class previously.
In this subgroup of patients, and when combined with fulvestrant, alpelisib was shown to extend median PFS to 11 months from 5.7 months for fulvestrant alone. Validating PIK3CA as a target, no benefit was seen in a small cohort of patients without a relevant mutation who were also enrolled in SOLAR-1.
Immunotherapy threatens to shift the paradigm for RCC again
Immunotherapy continues to have a dynamic effect in changing the treatment landscape for first-line renal cell carcinoma (RCC). A year ago at the ESMO 2017 Congress, compelling data for Bristol-Myers Squibb's combination of Opdivo and Yervoy - a PD-1 inhibitor and CTLA-4 inhibitor, respectively - were presented. Subsequent to FDA approval in April for the treatment of intermediate- and poor-risk advanced RCC patients, adoption of this regimen has reportedly been rapid.
US oncologists should shortly have another therapeutic option to reach for, with data from Pfizer and Merck KGaA's JAVELIN Renal 101 study showing that the combination of Bavencio (their PD-L1 inhibitor) and Inlyta (Pfizer's tyrosine kinase inhibitor) produced impressive PFS survival data in both PD-L1 positive and negative patients.
And further change could be afoot in the near term; just a day before this year's ESMO meeting kicked off, Merck & Co. confirmed its own study of Keytruda and Inlyta had met both the PFS and OS endpoints at a first interim analysis. On the conference side-lines, the company told FirstWord they also expect their data to be practice changing.
TRK tracking well still
In little over a month's time, the FDA is expected to approve Loxo Oncology and Bayer's larotrectinib, a TRK inhibitor in development for locally advanced or metastatic solid tumours that have an NTRK gene fusion, irrespective of histology. Additional data from an expanded cohort presented in Munich on Sunday indicate that approval should carry little doubt, with larotrectinib demonstrating an 81 percent objective response rate (ORR) across 109 adult and paediatric patients with TRK fusion cancers; importantly with responses consistent by age and tumour site. Furthermore, results demonstrated a median PFS of 28.3 months with median durability of response yet to be met; the first patient treated with larotrectinib is still receiving therapy 41 months later.
Nevertheless, two potential headwinds have threatened commercial enthusiasm for larotrectinib; a recent lowering of the estimated frequency of NTRK gene fusions across various cancer types and the pending release of data for Roche's entrectinib, an inhibitor of multiple tyrosine kinases, which has previously shown impressive efficacy in ROS-1 positive non-small-cell lung cancer.
Those initial data were also presented at the ESMO 2018 Congress on Sunday and while showing a "solid" ORR of 57 percent across 54 adult patients, these results "cannot be considered outstanding," wrote analysts at Credit Suisse. Furthermore, while entrectinib can cross the blood brain barrier, larotrectinib has also been shown to significantly reduce the volume of CBS lesions.
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