October 2017 Edition Vol.11, Issue 9

ESMO Trials Credited with Changing Standards of Care

By Ted Bosworth

Based on a wave of new clinical trial data, standards of care are likely to be changed in EGFR-positive lung cancer, metastatic renal cell carcinoma (mRRC), resectable stage III melanoma, ovarian cancer, and advanced breast cancer. For each of these diseases, the data presented at the 2017 meeting of the European Society of Medical Oncology (ESMO) produced the same refrain: “practice changing.”

Now typical of advances in treatment of cancer, a checkpoint inhibitor was the key therapy in several of these trials, but targeted therapies also continue to displace previous standards. Often the efficacy advantage with targeted drugs, unlike checkpoint inhibitors, is achieved with relatively low risk of major adverse events. This was true of a third generation tyrosine kinase inhibitor (TKI) for EGFR-positive lung cancer, a combination of TKIs for stage III melanoma, a PARP inhibitor for advanced ovarian cancer, and CDK 4/6 inhibitors in breast cancer.


EGFR-Positive Lung Cancer

For EGFR-positive lung cancer, the term practice changing was applied to osimertinib. The 37% overall survival (OS) advantage of osimertinib relative to currently used therapies has not yet reached the P value prespecified as proof of an advantage (P=.0015), but it was close (P=.0068), and other outcomes in the study were compelling.

“We think that osimertinib should be the new standard of care TKI,” said Suresh Ramalingam, MD, of Emory University’s Winship Cancer Institute, Atlanta, Georgia. He attributed the nearly doubling of progression-free survival (PFS) to the fact that osimertinib inhibits the T790M resistance mutation, which is what typically defeats the current first-line TKIs, gefitinib and erlotinib, over the course of treatment.

In the global osimertinib trial, called FLAURA, 556 patients with EGFR-positive non-small cell lung cancer (NSCLC) were randomized to once-daily osimertinib in a dose of 80 mg or, by investigator choice, a standard-of-care, once-daily TKI, which could have been gefitinib (250 mg) or erlotinib (150 mg). Patients with neurologically stable brain metastases were eligible.

The median PFS, which was the primary endpoint of the trial, was 18.9 months for the patients randomized to osimertinib versus 10.2 months in the arm receiving one of the current standard-of-care TKIs. This provided a hazard ratio (HR) 0.46 (P<.001). In graphs provided by Dr. Ramalingam, the curves separated early. Moreover, the relative advantage of osimertinib in the 116 patients who entered with brain metastases was similar to that in the study overall (HR 0.47; P=.0009).

Although the objective response rate (ORR) favoring osimertinib was not significantly greater (80% vs 76%), Dr. Ramalingam stressed that the duration of response was slightly more than doubled (17.2 mos vs 8.5 mos). In a comparison of non-Asian to Asian patients, which represented about 60% of those enrolled, the relative advantage for osimertinib was similar.

Grade 3 or greater adverse events were somewhat less common in osimertinib than the standard-of care agents (34% vs 45%, respectively) as were adverse events leading to discontinuation (13% vs 18%, respectively), although Dr. Ramalingam characterized the overall safety of all three TKIs as “generally comparable.”

Osimertinib is now licensed for EGFR-positive NSCLC, but Dr. Ramalingam concluded that it should be moved ahead of erlotinib and gefitinib into first-line therapy. An ESMO-invited discussant, Enriqueta Felip, MD, Head or the Thoracic Cancer Group at Vall d’Hebron Institute of Oncology in Barcelona, Spain, agreed.

“The drug was well tolerated and it has activity in the brain. Based on these results, osimertinib should be considered a new first line treatment option in NSCLC patients with EGFR mutations,” she said.


First Therapy to Beat Sunitinib in mRCC

A combination of the checkpoint inhibitors nivolumab and ipilimumab provided superior OS than the prior first-line therapy for advanced renal cell carcinoma (RCC) in the CheckMate 214 trial. As has been seen in other immunotherapy trials, the advantage

of the checkpoint inhibitors over the TKI sunitinib was observed in those with high or low expression of the checkpoint PD-L1, which is the target of nivolumab.

“These results support the use of nivolumab and ipilimumab as a new first-line standard-of-care option for patients with advanced renal cell carcinoma,” maintained the principal investigator of Checkmate 214, Bernard Escudier, MD, PhD, a medical oncologist with the Genitourinary Group, Institute Gustave Roussy, Villejuif, France. He noted that the OS advantage was accompanied by better

symptom control and lower Grade 3 or greater treatment-related adverse events than sunitinib.

In CheckMate 214, 1096 patients with advanced or metastatic clear-cell RCC were randomized to a combination of 3 mg/kg nivolumab and 1 mg/kg ipilimumab administered by infusion at scheduled intervals or to 50 mg daily sunitinib taken orally. OS and PFS were co-primary endpoints. The median follow-up was 25.2 months.

On an intent-to-treat (ITT) basis, the median OS was not reached for the immunotherapy versus 26 months for sunitinib (HR 0.68; P=.0003). Although the PFS was almost identical for the two treatment arms when compared on an ITT basis (12.4 mos vs 12.3 mos, respectively), both the OS (HR 0.63; P<.0001) and the PFS (HR 0.82; P=.0331) were superior for the combined checkpoint inhibitors in patients with poor to intermediate risk. The rate of Grade 3 or higher adverse events was 46% on immunotherapy versus 63% on sunitinib.

In mRCC, “sunitinib has never been defeated before by another therapy in a randomized phase 3 study,” observed Manuela Schmidinger, MD, Program Director, Renal Cell Carcinoma, Medical University of Vienna Austria. She agreed that this immunotherapy combination is reasonably considered a new standard of care.


Adjuvant Therapy for Resectable Melanoma Validated

Two major trials have validated adjuvant therapy after surgical resection for stage III melanoma, creating new and possibly competing standards of care in at least some patients with this cancer. Both trials, published on-line by the New England Journal of Medicine in conjunction with the ESMO presentations, associated adjuvant therapy with large OS benefits.

In the trial called COMBI-AD, enrollment was restricted to patients with BRAF V600 mutations. The adjuvant therapy was a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, which was compared with placebo in 870 patients. The primary endpoint was relapse-free survival (RFS). At 3 years, RFS was 58% in the group receiving the combined TKIs versus 39% in the placebo group (HR 0.47; P<.001). The OS at 3 years was 86% versus 77% (HR 0.57; P=.0006), reported Axel Hauschild, MD, professor of dermatology, University of Kiel, Germany.

In the other trial, called CheckMate 238, the enrolled population was similar but not identical to that of COMBI-AD. Of the most important differences, only 45% of patients had a BRAF mutation. RFS was again the primary endpoint.

After a median followup of 19.5 months, the 12-month RFS was 70.5% on nivolumab versus 60.8% with ipilimumab (HR 0.65; P<.001). There was no difference between arms for OS in this study of 906 randomized patients. However, the principal investigator, Jeffrey Weber, MD, Deputy Director, Perlmutter Cancer Center, New York University, New York City, emphasized that CheckMate 238, unlike COMBI-AD, compared the experimental with another active treatment rather than placebo.

“A previous trial found that ipilimumab had a significant RFS and OS advantage over placebo as an adjuvant therapy. CheckMate 238 shows that nivolumab is superior to ipilimumab,” according to Dr. Weber. He believes nivolumab should now be considered the new standard, although he conceded that the dabrafenib plus trametinib combination might also be a reasonable option in patients’ positive for a BRAF mutation.

This is controversial and may be interpreted differently in Europe than in the U.S., contended Reinhard Dummar, MD, Department of Dermatology, University of Zurich, Switzerland. He called both COMBI-AD and CheckMate “extremely encouraging,” but he cautioned against cross-trial comparisons. While he agreed that nivolumab showed impressive activity, the COMBI-AD trial results in BRAF-mutant melanoma are similarly compelling, and patients are likely to perceive TKIs as more convenient.


New Treatment Standards Declared in Ovarian and Breast Cancer

The PARP inhibitor rucaparib and the CDK 4/6 inhibitor abemaciclib were identified as potential new standards of care options in important subgroups of ovarian cancer and breast cancer, respectively, based on large multinational trials.

In ARIEL3, 564 women with high-grade ovarian cancer who had progressed after a second- or third-line platinum-based chemotherapy were randomized to rucaparib maintenance or placebo. A BRCA mutation was not required for entry. Relative to PFS in the placebo group (5.6 mos), PFS was more than doubled in patients with BRCA wild type disease (13.6 mos, HR 0.32; P<0.0001) and BRCA mutated disease (16.6 mos, HR 0.23; P<0.0001).

The PARP inhibitor olaparib is already licensed in many countries for maintenance therapy in BRCA mutated ovarian cancer, but rucaparib, if approved, may expand the role of these therapies by extending the indication to women without a BRCA mutation, according to Jonathan Ledermann, professor of oncology, UCL Cancer Institute, London. He considers rucaparib a potential standard for this indication.

In MONARCH3, 493 postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer who had no prior systemic therapy for this indication were randomized to abemaciclib plus the aromatase inhibitor anastrozole or anastrozole alone. The study was stopped at an 18-month interim analysis when the risk of progression was already reduced by almost half (HR 0.53; P=.000021) in the group receiving abemaciclib (PFS not reached vs 14.7 mos on anastrozole alone).

Although this is the third CDK 4/6 inhibitor to show an advantage over an aromatase inhibitor alone in this setting, the principal investigator, Angelo DiLeo, MD, Head, Sandro Pitigliani Medical Oncology Unit, Prato, Italy, suggested that this trial consolidates evidence that CDK 4/6 inhibitors are now a standard.

The ESMO invited discussant, Giuseppe Curigliano, MD, Director, Division of New Drug Development, European Institute of Oncology, Milan, Italy, agreed.

Many postmenopausal women with hormone-positive, HER2-negative, metastatic breast cancer “still receive chemotherapy, despite guidelines and data from clinical trials,” he said. “This study confirms we should avoid routine chemotherapy in this population.”



Editor’s Note: Shortly before we went to press the FDA approved abemaciclib (Verzenio, Eli Lilly) making it the third in a new class of CDK 4/6 inhibitors to be approved for breast cancer. For what’s unique about abemaciclib’s approval, see the FDA’s Sept. 28 announcement: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm

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