The field of oncology has seen a number of significant advances in recent years. The considerable number of positive reports from the 2019 Congress of the European Society for Medical Oncology (ESMO) last month clearly reflected the meeting’s theme — the translation of scientific advances into better cancer care.
AstraZeneca/Merck was one of stars of this year’s meeting, presenting pivotal Phase 3 data that showed improvements on overall survival across lung cancers as well as breaking new ground in the treatment of ovarian, prostate and pancreatic cancers.
We were particularly impressed by these partners’ success with their PARP inhibitor Lynparza (olaparib) in newly diagnosed advanced ovarian cancer. The companies presented detailed results from the Phase 3 PAOLA-1 trial of Lynparza plus Genentech/Roche’s Avastin, the current standard-of-care, versus Avastin alone in the first-line maintenance setting. Addition of Lynparza to the standard treatment reduced the risk of disease progression or death by 41% and improved progression-free survival to a median of 22.1 months, versus 16.6 months for Avastin therapy alone. Moreover, adding Lynparza did not increase the side effects seen compared to Avastin plus placebo. These results were irrespective of the patients’ genetic biomarker status or outcome from previous surgery, and thus closely reflect the general population of women with advanced ovarian cancer. This is the second successful Phase 3 trial of Lynparza in the first-line maintenance therapy setting for advanced ovarian cancer and shows the drug’s considerable potential to changing clinical practice for this disease.
Lynparza is currently approved in 64 countries for the maintenance treatment of platinum-sensitive, relapsed ovarian cancer. Lynparza is also currently used after chemotherapy to treat metastatic HER2-negative breast cancer with an inherited BRCA1 or BRCA2 mutation. Data presented at ESMO from the PROfound trial in men with previously treated, castration-resistant prostate cancer suggests that Lynparza may soon add a third tumor type to its approved uses. Results of this trial in second-line prostate cancer showed that Lynparza significantly extended progression-free survival in men with either BRCA1/2 or ATM mutations, resulting in a 3.8-month survival advantage and 66% reduction in the risk of progression compared to patients re-treated with front-line hormonal agents Xtandi or Zytiga. These patients, who represent up to 22% of prostate cancer patients, went 7.4 months without disease progression on Lynparza. AstraZeneca/Merck is conducting further analysis of Lynparza with respect to other genetic biomarkers in hopes of broadening the potentially responsive patient population.
Merck reported a major advance for Keytruda as neoadjuvant therapy for triple negative breast cancer — a new treatment setting for the immuno-oncology drug. Results from the Keynote-522 trial showed that treating patients with Keytruda and chemotherapy prior to surgery spurred more pathological complete responses than chemotherapy alone — 64.8% of patients receiving the combo showed no sign of residual cancer, regardless of their PD-L1 levels, compared to 51.2% of those who received chemotherapy alone. A pathological complete response prior to surgery is considered to be a good predictor of long-term outcomes.
Keynote-522 also looked at Keytruda’s ability to reduce the risk of disease recurrence and progression following surgery. Patients who received Keytruda prior to surgery also received it afterward, while those receiving only chemotherapy received placebo post-surgery. While long-term follow-up for this portion of the Keynote-522 is still underway, an interim look at 15.5 months post-surgery showed that risk of recurrence in the Keytruda-treated patients was reduced by 37% compared to the control group. This figure was not yet statistically significant, but the investigators found it encouraging as the interim look came early in the trial. Moreover, this data was sufficiently positive to win Keytruda a breakthrough therapy designation in this indication.
Multiple presentations at ESMO also continued to add to the evidence that blood-based biomarkers have predictive utility in non-small cell lung cancer (NSCLC). We were especially interested in two presentations by investigators from the FLAURA trial of AstraZeneca’s Tagrisso (osimertinib) versus current standard of care with tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC. Using data from FLAURA, they showed that longitudinal monitoring of circulating tumor DNA (ctDNA) could identify patients with advanced NSCLC who are likely to progress post-treatment.
The investigators evaluated plasma samples collected from 122 patients at specifically designated time points during the trial for several EGFR mutations (Ex19del, L858R and T790M, and C797S). To define ctDNA-based tumor progression (ctDNA progression), investigators quantified changes in ctDNA mutations detected in the samples. In 66% of patients, ctDNA progression was observed prior to disease progression by a median of 2.7 months. Acquired C797S or T790M mutations, markers of resistance to EGFR inhibitors, were detected in 47% of the patients with ctDNA progression. These acquired mutations could be detected either at the same time or before disease progression (with a median of 1.4 months sooner in 38% of the patients). The investigators concluded that ctDNA monitoring may allow both the earlier identification of patients who progress on first-line EGFR-TKI therapy as well as the early detection of EGFR-mediated resistance prior to disease progression in EGFR-mutated NSCLC.