ESMO Presidential Symposia Medscape Oncology

Coverage from the European Society for Medical Oncology (ESMO) Congress

Medscape Oncology
COMMENTARY
Clinical Takeaways From the ESMO Presidential Symposia

Stefan Zimmermann, MD
Disclosures | October 10, 2016

Pembrolizumab First-Line Beats Chemo: 'It's a New Day for Lung Cancer'
Prolonged Survival With Adjuvant Ipilimumab in Stage 3 Melanoma
Ribociclib Offers 'Paradigm Shift' in Advanced Breast Cancer

Editor's Note:
ESMO promised practice-changing clinical trials at their annual congress this year, and the final program delivered, particularly in lung cancer.

Throughout ESMO 2016, Stefan Zimmermann, MD, has been contributing his perspectives on the most important trials at ESMO to Medscape's ESMO 2016 Live Blog,

Below are Dr Zimmermann's clinical takeaways on three of these trials, presented during the first two Presidential Symposia at ESMO 2016. They are preceded in each case by a brief introduction to the study data.


Lung Cancer

The Presidential Symposia featured two important trials on immunotherapy in lung cancer, including a landmark trial of pembrolizumab alone as first-line therapy and new data on pembrolizumab plus chemotherapy, also in the first-line setting.

The data on first-line pembrolizumab in non–small-cell lung cancer (NSCLC) come from the first 305 patients enrolled in the phase 3 KEYNOTE-024 study,[1] presented by Martin Reck, MD, PhD, and published simultaneously in the New England Journal of Medicine.

This study was conducted in patients whose lung cancer biopsies showed no EGFR or ALK mutations and showed high expression of programmed death-ligand 1 (PD-L1) (defined as expression in 50% of tumor cells).

In this patient population, pembrolizumab alone gave superior results to platinum-containing doublet chemotherapy—median progression-free survival (PFS) was 10.3 vs 6 months (hazard ratio [HR], 0.50). The secondary endpoint of overall survival (OS) was also significantly improved: The OS rate at 6 months was 80% vs 72% (HR, 0.60) and the 1-year OS rates were 70% vs 54%. Toxicity was lower with immunotherapy compared with chemotherapy as well (grade 3/4 adverse events, 27% vs 53%).

The other data on pembrolizumab plus chemotherapy in the first-line setting come from a small phase 2 trial of 123 patients in the KEYNOTE-021 study,[2] presented by Corey Langer, MD, from the University of Pennsylvania.

This study was conducted in patients with squamous NSCLC who were not selected on the basis of PD-L1 expression, so it is a bigger patient population than the pembrolizumab-alone study—but again, patients with EGFR and ALK mutations were excluded. Pembrolizumab was added onto the chemotherapy doublet of carboplatin plus pemetrexed, and compared with chemotherapy.

The addition of pembrolizumab improved PFS to 13.0 vs 8.9 months (HR, 0.53; P = .0102), but it also added to toxicity (grade 3 or higher, 39% vs 26%).

In KEYNOTE-024, a randomized trial of pembrolizumab vs platinum-based chemotherapy in patients with previously untreated advanced NSCLC with high PD-L1 expression (> 50%), pembrolizumab produced a higher response rate, longer median PFS, and longer median OS despite a 50% crossover rate.

The HR for PFS was 0.5, with a median PFS of 10.3 months in the pembrolizumab arm vs 6.0 months in the chemotherapy arm. The HR for death was 0.6, and median OS has not been not reached. It is a understatement to say that thoracic oncologists are not used to HRs in this range. To complete the fairy tale, tolerability was in favor of pembrolizumab, with only 26% grade 3/4 adverse events.

We do indeed have a new standard of care for this subgroup of patients with high expression of PD-L1. Yet the discussant, Jean-Charles Soria, MD, PhD, raised a very valid point: The portion of patients who can benefit from upfront immunotherapy desperately needs to be enlarged. If 1934 patients are screened but only 500 patients are randomized, it means we treat about 1 out of 4 of our everyday patients. On a positive note, he highlighted the response rate of 44%—a record in the first-line setting—and the HR was a record low of 0.35 in the squamous subgroup.

The future might well belong to combinations, with early-phase trial results—KEYNOTE-021, for instance—hinting at combinations massively outperforming monotherapy.

Corey Langer, MD, presented the results of cohort G from KEYNOTE-021, a randomized phase 2 trial. The response rate reached 55% in the combination arm vs 29% for chemotherapy alone. Median time to response was 1.5 months—much faster than with chemotherapy alone. The response rate reached a whopping 80% in PD-L1 high expressors. PFS was massively increased, with an HR of 0.53 and a median PFS of 13.0 vs 8.9 months. Of note, response rates were similar for PD-L1–positive and PD-L1–negative patients. These phase 2 findings must be confirmed by the sister phase 3 trials KEYNOTE-189 (platinum/pemetrexed with or without pembrolizumab in nonsquamous tumors) and KEYNOTE-407 (carboplatin/paclitaxel with or without pembrolizumab in squamous tumors).

The landscape is changing faster than we can fathom.


The landscape is changing faster than we can fathom. We barely got used to the idea of pembrolizumab as first-line therapy in high expressors. Phase 3 trials will also provide insight into subgroups.

The million-dollar question now is whether chemotherapy is necessary at all in PD-L1–low subgroups, and whether pembrolizumab monotherapy can be beaten. Can we move to a chemotherapy-free regimen for most patients?

The answer may reside in the combination of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1/PD-L1 checkpoint blockade. This is currently being pursued in at least three trials: CheckMate 227, NEPTUNE, and MYSTIC. CheckMate 227 is two studies, actually; PD-L1–positive patients are randomly assigned to receive ipilimumab plus nivolumab vs nivolumab alone vs chemotherapy, whereas PD-L1–negative patients are randomly assigned to two different schedules/doses of nivolumab plus ipilimumab, or to chemotherapy.

NEPTUNE is testing durvalumab plus tremilimumab vs chemotherapy, and MYSTIC is testing durvalumab alone, vs durvalumab plus tremelimumab, vs chemotherapy. Missing in these trials is a chemotherapy plus chemotherapy arm, which might now well be the adequate comparator arm


Breast Cancer

Ribociclib is a new cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for use in combination with letrozole in patients with metastatic hormone-dependent breast cancer that is HER2-negative. It is a similar drug to the recently approved palbociclib (Ibrance®; Pfizer).

Interim results from the MONALEESA-2 study[3] presented at ESMO 2016 indicate that adding ribociclib to letrozole improves PFS by 44% and significantly improves overall response to therapy. After a median follow-up of 15.3 months, ribociclib was associated with a significant improvement in PFS, with an HR of 0.556 (P = 3.29 × 106). This corresponded with a median PFS of 14.7 months in the placebo arm, whereas median PFS was not reached in the ribociclib arm.

Among patients with measurable disease at baseline, the overall response rate was 52.7% with ribociclib vs 37.1% with placebo (P < .001). The clinical benefit rate was 80% and 72%, respectively (P = .02). The most common grade 3/4 adverse events reported in at least 5% of ribociclib and placebo recipients, respectively, were neutropenia (59% vs 1%), leukopenia (21% vs 1%), hypertension (10% vs 11%), and elevated alanine aminotransferase levels (9% vs 1%). Discontinuation rates because of adverse events were 7.5% and 2.1%, respectively. We have all been waiting for a serious strategy to delay acquired resistance to frontline antihormone therapy. And yet we know all too well that not just any combination with aromatase inhibitors is a step in the right direction: Despite a massive improvement in PFS, the combination of exemestane and everolimus is poorly tolerated, and enthusiastic oncologists are few. Enter ribociclib. The HR for PFS was 0.556, median PFS not reached (14 months in the letrozole alone arm). Neutropenia was very frequent, but febrile neutropenia rare. High-grade nonhematologic toxicity was rare. It looks like we have a serious contender after all. Good points from the invited discussant, Stephen Johnston, MD, PhD, from the Royal Marsden Hospital in London: The FALCON study presented this morning during the breast cancer session demonstrated superior PFS with fulvestrant over the aromatase inhibitor anastrozole. Fortunately, MONALEESA-3 (ribociclib plus fulvestrant first-line/second-line) is fully accrued. Stay tuned. Also, the curves separated early: A large portion of patients derived a benefit, in contrast with the aromatase inhibitor-alone arm, where we witnessed a rapid fall at the beginning of the PFS curve. Ribociclib results are in line with those for albociclib in the same setting, studied in the PALOMA-2 trial. It seems we actually have two good drugs to combine with first-line letrozole. Dr Johnston's conclusion: It is a game changer.