ESMO 2016 | Educational Session – HL: How to incorporate novel therapies into the treatment?

This year’s ESMO annual congress took place on 7–11 October in Copenhagen, Denmark, and is considered the most important European scientific platform where oncology research can be presented, uniting researchers, clinicians and patients to find the most effective cancer management and treatment strategies today.

During an Educational Session on 8^th October, Professor Peter Johnson, Cancer Research UK and University of Southampton, gave a talk titled: “how to incorporate novel therapies into the treatment of Hodgkin’s Lymphoma (HL)?”

Professor Johnson began by giving an overview of the cure rate of current therapies by stating that 90% of early stage HL patients and 75% of advanced stage HL patients are cured with first line therapy, resulting in an average cure rate of 80% for all HL patients. He went on to say that greater than 80% of patients with HL are alive at 10 years and that improving this result, as well as minimizing acute and long-term toxicity of treatment, are the primary aims of research. So, where do novel agents fit in?

The talk then began to discuss which patient groups need more effective treatment. Professor Johnson elaborated that older patient groups do not do so well; as age increases, survival rate decreases.

Professor Johnson then moved on to discuss overall findings in trials treating patients with early stage disease, which are:

• Chemotherapy improves the cure rate over radiation alone
• Reducing the radiation field appears to have a good safety profile
• Reducing the radiation dose is possible for good prognosis disease, or after adequate chemotherapy
• Omitting radiotherapy altogether may be possible for many patients using interim FDG-PET to select them

Following on from this last point, Professor Johnson then outlined the design of the UK NCRI RAPID trial; a randomised phase III trial aiming to determine the role of FDG-PET imaging in clinical stages IA/IIA HL patients (NCT00943423).

During this trial, among patients who were PET negative, an Intention-To-Treat (ITT) analysis was performed which included 420 patients who underwent randomization. 3-year Progression Free Survival (PFS) was 94.6% (95% CI, 91.5­–97.7%) in the radiotherapy group and 90.8% (95% CI, 86.9–94.8%) in the group with no further therapy. 3-year Overall Survival (OS) was lower in the radiotherapy group than the no further therapy group; rates were observed as 97.1% (95% CI, 94.8–99.4%) and 99.0 % (95% CI, 97.6–100%), respectively. Professor Johnson also drew attention to the 87.6% PFS rate, which was achieved amongst PET positive patients and asked: could we do better?

Early stage disease was summarized by emphasizing that early HL is highly curable, but life after cure is a key consideration. Omission of radiotherapy after a negative early FDG-PET scan will slightly increase the rate of recurrence by approximately 5% but probably will not affect survival. Increasing intensity for PET positive patients is effective. However, Professor Johnson asked if new agents could improve this and also increase the PET negative rate.

Professor Johnson then moved on to discuss data he and his colleagues published in the Journal of Clinical Oncology back in 2005, which compared ABVD and alternating or hybrid Multidrug Regimens (MDR) for treating advanced HL. The paper concludes that no significant difference between Event Free Survival (EFS) or OS between the ABVD and MDR groups was found in the trial overall and so ABVD remained the treatment standard for advanced HL.

A systematic review and meta-analysis by Skoetz et al., published in Lancet Oncology in 2013, was then discussed. This analysis found that OS was highest in patients who were treated with six cycles of BEACOPP_escalated, which also had a higher 5-year survival rate compared to ABVD (95% vs 88%). Reconstructed individual survival data at 5 years showed that BEACOPP_escalated has a 10% OS advantage over ABVD. Peter Johnson also covered the HD15 trial, where in the ITT, 711 patients treated with 6 cycles of BEACOPP_escalated where compared to 705 patients treated with 8 cycles of BEACOPP_escalated and 710 patients were treated with 8 cycles of BEACOPP₁₄. OS in the three groups was 95.3%, 91.99% and 94.5%, respectively, and was significantly better with 6 cycles rather than 8 cycles of BEACOPP_escalated. 8 cycles also resulted in higher mortality than 6 cycles (7.5% vs 4.6%). Based on these results, the group recommend 6 cycles of BEACOPP_escalated should become treatment of choice for advanced stage HL. However, Peter Johnson points out that they make no direct comparison to ABVD and also states that any comparisons that have been made produce conflicting data.

The talk then turned to summarizing the role of escalated therapy and FDG-PET in treating advanced stage HL

• After a negative interim FDG-PET scan it is possible to omit bleomycin from subsequent cycles as this reduces toxicity
• Escalated therapy for interim FDG-PET positive patients gives reasonable, but not ideal, subsequent response and PFS results (70% 3-year PFS for PET-3 negatives)
• The ‘false-negative’ rate for interim FDG-PET is higher in patients with more advanced HL
• Areas of need include initial therapy for high risk cases and therapy for interim PET-positive cases

The role of brentuximab vedotin, an antibody-drug conjugate, in treating advanced HL was explored. A phase II study by Younes et al., published in the Journal of Clinical Oncology, was discussed which observed tumor reductions in 94% (96/102) of patients. Results of a recent trial by Chen et al., published in Blood (NCT00848926), was also presented which found that 38% (13/34) of relapsed or refractory (R/R) HL patients who achieved a Complete Response (CR) when treated with brentuximab vedotin have remained in remission for more than 5 years. Moreover, 9 of these 13 patients have remained in long-term remission without the need for consolidation with an allogeneic transplant.

Professor Johnson then gave an update on the ECHELON-1 trial (NCT01712490), a phase III, randomized, open-label trial of brentuximab vedotin combined with doxorubicin, vinblastine and dacarbazine (A+AVD) versus ABVD in patients with advanced classical HL.  

The AETHERA trial was also discussed, a phase III trial of brentuximab vedotin in post-ASCT HL patients, which found by independent review that brentuximab vedotin had a superior median PFS compared to patients in the placebo group (42.9 months vs 24.1 months). 

Activity of Nivolumab and pembrolizumab, humanized monoclonal antibodies that block the PD-1 pathway, was the last topic covered in Professor Johnson’s talk. Work by Ansell et al. published in The New England Journal of Medicine (NCT01592370) and presented at ASH 2015 has found that nivolumab has substantial therapeutic activity and is well tolerated in patients with relapsed or refractory classical HL. Armand et al., who published results in the Journal of Clinical Oncology, found a CR rate of 16%, a Partial Remission rate of 48%, an Overall Response rate of 65% and a PFS of 46% at 52 weeks in classical HL patients treated with pembrolizumab after brentuximab vedotin failure. The group conclude that pembrolizumab has a favourable safety profile and induces favourable responses in heavily pre-treated patients.

Professor Johnson rounded off this detailed talk with a simple and concise conclusion:

• HL is highly curable
• For most patients, this is achieved with conventional therapies
• However, efficacy can still be improved, especially for elderly patients
• Response-adapted therapy helps to balance efficacy and toxicity
• New agents are currently being explored for first-line and recurrent disease
• Populations of patients for study are being identified using cytogenetics, expression profiling, prognostic factors and interim PET imaging