ESMO Opens with Survival Benefits from Long-Term Data in Pivotal Phase III Trials

The 2019 European Society of Medical Oncology (ESMO) opened with a series of trials with positive overall survival (OS) data. Generally considered the gold standard for practice change, survival benefits were associated with osimertinib in the FLAURA lung cancer trial and two different CDK 4/6 inhibitors in the MONARCH 2 and MONALEESA-3 breast cancer trials. New five-year data from the CHECKMATE 067 trial did not just reaffirm a survival advantage for combination checkpoint inhibitors in metastatic melanoma but a potential advantage for disease cure.

FLAURA: EGFR-Mutation NSCLC

In EGFR-mutation positive non-small cell lung cancer (NSCLC), new data from the FLAURA trial have confirmed that starting with the third-generation tyrosine kinase inhibitor (TKI) osimertinib is a better strategy than starting with a second-generation TKI. Osimertinib produced a survival benefit even though those initiated on the second-line TKIs were permitted to crossover at the time of progression.

“This is the first time that a survival benefit has been shown for one TKI over another in NSCLC,” said Suresh S. Ramalingam, MD, Winship Cancer Institute, Emory University, Atlanta, Georgia.

Patients randomized to second-line TKIs were permitted to take either gefitinib or erlotinib. Osimertinib was superior to these drugs for the primary endpoint of progression-free survival (PFS) in FLAURA data published last year (Soria et al. N Engl J Med 2018;378:113-125). On the secondary OS outcome, osimertinib provided a more than six-month relative advantage (38.6 vs. 31.8 months; P=0.0462) and a greater than 20% risk reduction (HR 0.799; P=0.0462).

The fact that patients in the comparator arm were allowed to switch at progression is critical for interpreting the results, according to the Pasi A. Jänne, MD, PhD, Dana-Farber Cancer institute, Boston. It shows that sequencing of TKIs is suboptimal. Rather, Dr. Jänne said, “you should use the best drug first.”

These data will change practice where drug sequencing is still being performed, but Dr. Jänne said that the PFS advantage had already convinced most physicians in the U.S. to use osimertinib first. One reason, as demonstrated in the FLAURA control arm, is that about one third of patients with EGFR mutation-positive advanced NSCLC never receive a second drug.

MONARCH 2 and MONALEESA-3

In hormone receptor positive/HER2-negative advanced breast cancer, two trials have shown an OS advantage for a CDK 4/6 inhibitor plus the estrogen-receptor antagonist fulvestrant relative to fulvestrant plus placebo.

The data from the two trials, MONARCH 2 and MONALEESA-3, are complementary, according to Nadia Harbeck, MD, University of Munich, Germany. Based on these data, she concluded this combination should now be considered “a standard of care” in this setting.

In the similarly designed MONARCH 2 and MONALEESA-3 studies, patients were randomized in a 2:1 ratio to a CDK 4/6 inhibitor plus fulvestrant or to the control arm. The CDK 4/6 inhibitor was abemaciclib in MONARCH 2 and ribociclib in MONALEESA-3, which, unlike MONARCH 2, limited enrollment to postmenopausal patients.

The OS advantage from adding a CDK 4/6 inhibitor to fulvestrant in the MONARCH 2 and MONALEESA-3 trials joins a previously reported OS advantage from ribociclib plus fulvestrant relative to fulvestrant alone in the MONALEESA-7 trial. Enrollment in the MONALEESA-7 trial was limited to premenopausal women and published earlier this year (Im SH et al. N Engl J Med 2019;381:307-316).

In MONARCH 2, which randomized 669 patients with HR+/HER2-breast cancer, the median OS was increased 9.4 months (46.7 vs. 37.3 months) after a median followup of 47.7 months, translating into a 22% relative advantage for abemaciclib over placebo (HR 0.78; P<0.0001).

“This was not only statistically significant but I would argue clinically relevant and important to patients,” reported George W. Sledge, MD, Stanford University, Stanford, California.

In addition, being randomized to the CDK 4/6 inhibitor more than doubled the time to subsequent chemotherapy (50.2 vs. 22.1 months; P<0.0001).

In MONALEESA-3, 726 patients were randomized. About half were being treated for the first time. After a median followup of 39.4 months, the median OS has not been reached in the experimental arm versus 40.3 months in the control arm, producing a roughly 28% relative advantage for ribociclib over placebo (HR 0.724; P=0.0046).

Also citing the MONALEESA-7 trial, Dennis J. Slamon, MD, University of California, Los Angeles concluded that CDK 4/6 inhibitor plus endocrine therapy “provides a meaningful prolongation of survival regardless of menopausal status.”

CheckMate 067—50% Cure Rate of Metastatic Melanoma

In patients with metastatic melanoma, five-year outcome data from the CheckMate 067 study has confirmed greater survival and possibly greater rates of cure in those patients treated with the combination of ipilimumab plus nivolumab when compared with either checkpoint inhibitor alone.

At five years, the rates of OS for ipilimumab plus nivolumab, nivolumab alone, and ipilimumab alone were 52%, 42%, and 26%, respectively. Those alive and free from subsequent therapy, suggesting possible cure, were 35.7%, 23.7%, and 14.3%, respectively.

The OS rates at five years were similar on the combination of checkpoint inhibitors regardless of whether patients had BRAF mutant or wild-type tumors, whether or not PD-L1 expression was above or below 5%, and whether or not they discontinued therapy early due to adverse events.

Juxtaposed to the estimated 5% five-year survival for metastatic melanoma prior to the introduction of checkpoint inhibitors, the data from CheckMate 067 suggest that about one in two patients treated with a combination of these agents can expect to be alive at five years, according to the principal investigator, James Larkin, MD, Royal Marsden NHS Foundation Trust, London, UK.

However, the combination of checkpoint inhibitors is associated with significant toxicity. In the previously reported OS data at three years (Wolchok JD et al. N Engl J Med 2017;377:1345-1356), grade 3 or higher adverse events occurred in nearly 60% of patients. Dr. Larkin also cautioned that there are no current methods for predicting which of the sizeable proportion of patients will be exposed to these side effects but achieve no clinical benefit.

by Ted Bosworth

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