ASCO 2014: Gearing Up for More Changes

Andre Goy, MD

Editor-in-Chief of

Oncology & Biotech News

Chairman and Director Lymphoma Division Chief John Theurer Cancer Center at HackensackUMC Chief Science Officer and Director of Research and Innovation Regional Cancer Care Associates Professor of Medicine, Georgetown University

The ASCO annual meeting is always a time of excitement for the nearly 30,000 clinicians and scientists who gather every year to see “what’s new.” Once again—and maybe even in a more palpable way than ever before—this year’s ASCO meeting confirmed that huge changes are coming in oncology. While difficult to completely capture in this space, here are a few lessons that can be learned from the “2014 ASCO cru.”

1. How long will we continue to do huge randomized trials?

The ALTTO trial, which was presented at the plenary session, enrolled more than 8000 women in 44 countries with HER2-positive breast cancer after their tumors had been completely removed by surgery. The study aimed at determining the best way to inhibit HER2 (J Clin Oncol. 2014;32:5s [suppl; abstr LBA4]).

There were four arms: trastuzumab (monoclonal antibody anti-HER2/neu) alone; vs lapatinib (dual kinase inhibitor that targets Her2/neu and EGFR) alone (failed early); vs two arms using both agents either in combination or as sequential therapy.

On the basis of results in the activity of these drugs in the clinic as well as preclinical rationale, there was a lot of enthusiasm for the ALTTO study and high expectations; however, the trial was negative, with no improvement in disease-free survival or overall survival with the combination.

Another large study in breast cancer, the phase III APHINITY trial looking at pertuzumab (another anti- HER2/neu monoclonal antibody) with traztuzumab, just reached its recruitment target of nearly 5000 patients, with results still pending. APHINITY is the confirmatory trial for the accelerated approval of pertuzumab. In September 2013, the FDA approved pertuzumab in the neoadjuvent setting based on phase II data demonstrating improved pathologic complete response.

Though both studies are great endeavors in clinical research, this large-trial approach might become a real challenge moving forward. Given the number of novel therapies we have in the pipeline (>1500 easily in oncology), will it become impossible to do such trials where you need thousands of patients to detect a small but “meaningful” improvement?

This approach does not seem sustainable. Further, while subsets of patients might benefit from anti-HER2 combinations, whether enough biomarker studies are feasible in the setting of such large trials has to be reassessed. It seems we need new models to select patients, particularly to focus more on biomarkers/ signatures early on as part of phase II studies. This might allow a reduction in the study population, hopefully develop better molecular rationale for combinations, and hopefully speed up drug development.

2. In B-cell malignancies, are we going to develop other options to replace chemotherapy?

Over the last few years, a number of new biological agents have emerged, particularly in chronic lymphocytic leukemia (CLL) but also in non- Hodgkin lymphoma. Among the novel therapies, drugs targeting the BCR pathway, such as ibrutinib (BTK inhibitor) and idelalisib (PI3Kd inhibitor), have shown dramatic activity in CLL and in some lymphomas and are both oral oncolytics.

At ASCO, O’Brien at al (J Clin Oncol. 2014;32:5s [suppl; abstr 7014]) presented an independent evaluation and long-term update (3-year followup) of ibrutinib in CLL/SLL patients including 17p deletion. A total of 132 patients were treated, showing an overall response rate (ORR) of 78%, including 83.9% in treatment-naïve CLL and 77% in patients with relapsed/refractory (r/r) CLL. Overall, not only the treatment was very well tolerated, but the responses were very durable: the median duration of response (DOR) was not reached for alltreated patients and at 2 years, more than 85% had not progressed! If we focus on the worse subgroup in r/r CLL with del(17p) (who usually have a very poor outcome) the ORR was 55.9% and median DOR was 25 months for patients who had received a median of four prior therapies (range, 1-12)! A separate late-breaking abstract reported results from the phase III RESONATE trial, which compared oral ibrutinib with ofatumumab, an anti-CD20 monoclonal antibody in r/r CLL (J Clin Oncol. 2014;32:5s [suppl; abstr LBA7008]). Ibrutinib showed an almost 10-fold improvement in response rate, progressionfree survival, and even overall survival. Ibrutinib is now approved in r/r CLL and mantle cell lymphoma, where the ORR was 68% with a 20% complete response (CR) rate and a median DOR of 17 months.

The favorable safety profile of ibrutinib leads naturally to combination therapy with rituximab (R)—chemotherapy regimens that are ongoing (with BR, FCR, R-CHOP, etc), but also offers strategies for maintenance postchemotherapy.

One of the most promising aspects of these BCRtargeting therapies is the opportunity to develop non—chemotherapy based options. There are several trials ongoing, such as studies combining these investigational agents with rituximab or with rituximab/lenalidomide, or other biologicals that illustrate the paradigm change we are witnessing.

Also at ACSO, there was again very promising data shown using antibody-drug conjugates in r/r diffuse large B-cell lymphoma and particularly in Hodgkin lymphoma, where brentuximab vedotin (BV) has been approved in the r/r setting. In a pilot study, BV was used as frontline therapy. In patients with Hodgkin lymphoma who received two cycles of BV (as a window of opportunity), followed by three to six cycles of ABVD, depending on stage (radiation was given per physician decision; J Clin Oncol. 2014;32:5s [suppl; abstr 8507]). Results showed an ORR of 91%, with an 83% CR rate, after just two cycles of BV. Though BV is being tested in an ongoing phase III trial to replace bleomycin, these results suggest BV might even further change the landscape of Hodgkin lymphoma.

Numerous questions remain, but it is likely that in some B-cell malignancies, non-chemotherapy options will replace standard approaches, often offering oral and/or easier combinations for patients and improved outcomes.

3. Immunotherapy Continues to Impress

In an earlier column, I spent time on the amazing “new face of immunotherapy” in oncology (http:// bit.ly/OBTN_Feb). At ASCO, numerous presentations again confirmed the benefit of anti—CTLA-4 (ipilimumab), anti–PD-L1, and anti–PD-1 checkpoint inhibitors across a number of tumor types. For example, an update on melanoma data from last year showed a 70% overall clinical benefit rate, including 20% of these patients having durable CR and a median overall survival of almost 3.5 years in a population with a life expectancy before the treatment in the range of 6 months. Without any doubt, immunotherapy with checkpoint inhibitors or cell therapy (based on CAR-T cells) will be a game changer in the management of cancer patients.

The drastic changes in the oncology landscape are mind-blowing. As we go forward, we must not forget the cost of these medicines, particularly as we will be treating patients with novel combinations for long periods of time. As I mentioned in a previous column (http://bit.ly/OBTN_March), physicians need to be engaged in the quality of outcome and cost of care, and make smarter medicine the best medicine.