The multiple myeloma landscape is rapidly evolving, with the recent approval of Kyprolis (carfilzomib, Onyx) and the pending approval of pomalidomide (Celgene), both in the relapsed/refractory setting. We’ll see pivotal data for pomalidomide on Tuesday morning during ASH’s Late-Breaking Abstract session, but the first days of the conference have highlighted a few new mechanisms of action that are showing promising activity in multiple myeloma. Numerous other agents also are being investigated in the relapsed/refractory myeloma setting. Awareness of the changing myeloma landscape will be critical for anyone thinking about initiating new pivotal Phase III trials in this disease.
ARRY-520 (Array BioPharma) is a kinesin spindle protein inhibitor that is currently being developed in relapsed/refractory multiple myeloma patients. At ASH we saw the results of a dose-escalation study for ARRY-520 alone and in combination with dexamethasone (Shah, Abstract 449). The trial included highly relapsed patients who had failed prior Velcade and Revlimid and were heavily pretreated, with six to 10 prior regimens. The objective response rate (ORR) in the monotherapy arm was 16%, and in the combination arm the ORR was 22% (all partial responses). Considering these patients have failed so many prior treatment options, the 16% to 22% ORR is impressive; compare that with the 24% ORR achieved with Kyprolis monotherapy in patients with a median of five prior lines of therapy. Both the monotherapy and combination arms were very well-tolerated with low incidence of non-hematologic toxicities; neuropathy was not observed with ARRY-520 therapy. Most common hematologic toxicities for monotherapy included Grade 4 neutropenia (28%), thrombocytopenia (25%) and anemia (6%). In the combination arm, Grade 4 toxicities included neutropenia (38%), thrombocytopenia (19%) and anemia (5%). Biomarker studies identified AAG as a potential selection marker for response to ARRY-520, although this requires further confirmation, which is ongoing. Currently the drug is being evaluated in a new Phase I study in combination with Kyprolis or Velcade.
Another unique mechanism of action that has shown exciting results is elotuzumab (Abbott, BMS, Ono), which made its first splash at ASH 2011. Elotuzumab is a humanized monoclonal antibody against the surface glycoprotein CS1, which is expressed primarily on multiple myeloma cells. In a Phase II study, elotuzumab in combination with RevDex in relapsed/refractory patients demonstrated clinical activity with an ORR of 92% (including 14% CR) and 20.8-month median progression-free survival (PFS) in the 10 mg/kg dosing cohort (Richardson, Abstract 202). When compared with historical controls of RevDex in multiple myeloma, elotuzumab stands out with better response benefit and longer PFS, even in a more heavily pretreated patient population. Elotuzumab is currently being evaluated in combination with RevDex in two Phase III trials in first- and second-line myeloma.
Results were reported from a Phase I trial that evaluated the novel monoclonal antibody tabalumab (LY 2127399, Eli Lilly), which targets the membrane-bound and soluble B-cell activating factor (BAFF), a protein that is elevated in patients with multiple myeloma. The Phase I study evaluated the combination of tabalumab with Velcade (bortezomib, Millennium/Johnson & Johnson) in multiple myeloma patients who have relapsed after at least one prior therapy (Raje et al., Abstract 447). Of the 43 enrolled patients, the majority had received three or more prior therapies and almost all patients had relapsed after prior Velcade or an iMiD (Revlimid (lenalidomide, Celgene) or thalidomide); 75% had received prior Velcade. Overall the combination of tabalumab with Velcade/dexamethasone was very well-tolerated, with the most common Grade 3 or higher adverse events being thrombocytopenia (23%), pneumonia (10%) and peripheral sensory neuropathy (10%). The ORR was 45.8% and included two (4%) complete responders; an additional 21 patients achieved stable disease. The median time to progression (TTP) was 4.9 months, and duration of response was 7.3 months. It’s unclear at this time whether the responses seen can be attributed to tabalumab or to the Velcade combination partner; therefore, it will be key to gain better understanding of the trial patient population, especially the quality of their response to prior Velcade in order to assess the true value of this agent.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Neesha Suvarna, PhD, Consultant, Kantar Health
At SABCS, 2012 seemed to be the year for long-term follow-up data for a number of adjuvant therapies in resectable breast cancer treatment. In the HER2-positive setting, the final analysis was presented from the NASBP-31/NCCTG N9831 studies, the seminal studies that introduced adjuvant Herceptin® (trastuzumab, Genentech/Roche) as the standard of care. In addition, the duration of adjuvant Herceptin was solidified with the data from the HERA and PHARE studies, reprised from the European Society of Medical Oncology (ESMO) 2012 Conference, but there were a few pieces of new information. Beyond HER2, the analysis of 10 years versus five years of adjuvant tamoxifen in estrogen receptor (ER) positive patients from the ATLAS study was also a highlight of the conference.
Long-term results from the NASBP-31/NCCTG N9831 studies showed that the benefit of adjuvant Herceptin was durable with benefits in both disease-free survival (DFS) and overall survival (OS) persisting now beyond 10 years (Romond, Abstract S5-5). At 10 years out from randomization, adding Herceptin to adjuvant therapy showed an 11.5% improvement in DFS (73.7% versus 62.2%; HR=0.60, p<0.0001) and an 8.8% improvement in OS (75.2% versus 84.0%; HR= 0.63, p<0.0001). In this trial, one year of adjuvant Herceptin was somewhat arbitrarily chosen as the study regimen, leaving questions as to whether shorter or longer durations of Herceptin could be beneficial; questions answered in the HERA and PHARE studies (Abstracts S5-5 and S5-3).
A very brief summary of the findings (as the data was essentially the same as was presented at ESMO 2012) is that one year of adjuvant Herceptin will remain the standard of care. The HERA study showed that two years of Herceptin offered no additional benefit beyond what is achieved with one year of Herceptin, and the PHARE non-inferiority results showed that six months of therapy was inconclusive but potentially inferior to one year of Herceptin. A key point highlighted by both presentations was the need for significant long-term follow-up for any major practice-changing adjuvant therapy trial. In the HERA study, results at the four-year follow-up suggested that two years of Herceptin may have been beneficial in hormone receptor (HR) negative patients, but the newer eight-year follow-up data showed that the benefit was transient and there was a risk in over-treating patients and subjecting them to unnecessary cardiac toxicity.
Finally, the 10 years versus five years of adjuvant tamoxifen in ER-positive patients in the ATLAS study created a lively discussion at the symposium (Davies, Abstract S1-2). The data showed that 10 years of treatment was superior to five years, with the interesting caveat that the benefit does not show up until after the 10 years of therapy. The hazard ratio (HR) for the 10-year cohort versus the five-year in years five through nine was 0.97, no difference. But in the years after 10 (this was a 15-year follow-up) the HR improves to 0.71 (p=0.0016). It is currently unclear why the majority of the benefit is showing up after patients go off therapy, but this phenomenon is also observed in the five-year arm compared to placebo where the survival benefit continued to increase beyond the five years of therapy. Regarding toxicity concerns, 10 years of tamoxifen increased endometrial cancer mortality rates from 0.2% with five years of therapy to 0.4%. However, it was generally agreed that the benefit in breast cancer morality outweighed the risk of endometrial cancer mortality.
After the presentation was when the real debate began. It was immediately pointed out in the question and answer session that these results do not appear to be as favorable as the results of the NCIC CTG MA.17 study (Jin, J Clin Oncol 30:718-721, 2011), which looked at switching to five years of the aromatase inhibitor, Femara (letrozole, Novartis) after an initial five years on tamoxifen. Acknowledging that cross-trial comparisons are always a risky exercise, it was pointed out that tamoxifen showed no survival benefit in years five through nine of therapy, but the Femara trial showed a beneficial HR of 0.61 over that same period. This is a debate that will be hashed out in the clinic in the coming months and years, but aromatase inhibitors appear to be in a relatively strong position.
The common theme for all of these studies is that adjuvant therapy is improving outcomes in breast cancer and that can always be considered a positive result. Also, those patients who may be ineligible for aromatase inhibitors, will be able to benefit from the new 10-year tamoxifen standard of care. It is clear that long-term follow-up is the key for getting the most out of these adjuvant therapy studies.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Josh Garcia, Associate Consultant, Kantar Health
It was a little over one year ago that Novartis presented data showing that adding a targeted agent, the mTOR inhibitor Afinitor® (everolimus), to hormone therapy could significantly and dramatically prolong progression-free survival (PFS) in relapsed hormone receptor-positive post-menopausal breast cancer. With PFS nearly tripling (11.0 versus 4.1 months; HR 0.36, p<0.0001), the results were immediately regarded as practice-changing, and questions began to arise about the potential of adding targeted agents to earlier lines of hormone therapy and the toxicity costs of these combinations.
Enter the CDK 4/6 (cyclin-dependent kinase 4 and 6) inhibitor, PD 0332991 (Pfizer). The inhibitor is designed to shut down retinoblastoma (Rb) phosphorylation, which drives cell division. With very favorable preclinical activity, CDK inhibitors have been on key opinion leaders’ radars recently as very promising agents, and the results from the randomized Phase II combining PD 0332991 with Femara® (letrozole, Novartis) did not disappoint (Finn, Abstract S1-6, SABCS 2012). The study enrolled 165 first-line post-menopausal estrogen receptor (ER) positive breast cancer patients who had not been previously treated for advanced or metastatic disease. It is important to note that ER positivity was the specific biomarker for sensitive patients; this was independent of progesterone receptor (PR) status. As part of the trial design, CCND-1 amplification and p16 were prospectively evaluated as potential biomarkers, but only ER status was predictive of activity. At this interim analysis the addition of PD 0332991 to Femara compared with Femara alone increased median PFS from 7.5 months to 26.1 months (HR=0.37, p=<0.001)! The control arm underperformed somewhat in this study (historical PFS rates for first-line aromatase inhibitors are still in the nine- to 10-month range), but this still represents a significant improvement with PD 0332991. It’s notable that the majority of enrolled patients had rather aggressive disease (de novo metastatic disease or a short disease-free interval following adjuvant therapy), which may explain the underperformance of the control arm and further raise the meaningfulness of the PD 0332991 arm’s performance. A benefit in objective response rate (ORR) was also observed, but the magnitude did not approach the same levels as PFS benefit — ORR was 34% in the PD 0332991-containing arm and 26% in the Femara monotherapy arm. The discordance in ORR benefit and PFS benefit may be explained by CDK 4/6’s role in regulating mitotic progression, but not in mediating cell death. The mechanism may also explain why the clinical benefit rate in this breast cancer study was dramatically improved (CBR = 70% with PD 0332991+Femara versus 44% with Femara alone).
The caveat to all the fantastic efficacy data is that the CDK inhibitor did add some significant hematologic toxicity. Rates of Grade 3/4 neutropenia were increased from 1% to 51% and leukopenia from 0% to 14%. On study, 71% of patients required a dose interruption and 35% required a dose reduction; adverse events led to 10% of the discontinuations. However, the author noted that there were no cases of febrile neutropenia, and no administration of growth factors was required. It would appear that the hematologic toxicity could be considered significant but manageable. Ultimately, if the dramatic PFS benefit holds up in the Phase III study, physicians may be willing to deal with the toxicity.
Physicians’ perception of toxicity in first-line hormone therapy will be a key point to be understood going forward. Hormone therapy has always been considered a relatively benign treatment, and physicians usually try to keep women on hormone therapy as long as possible before switching to chemotherapy. While the addition of targeted therapy to hormone therapy is reducing that toxicity benefit, it seems as though the efficacy benefits are likely to outweigh toxicity when it comes to PD 0332991. Pfizer has announced plans for a Phase II/III study (NCT01740427) in the same patient population and anticipates initiation in February 2013. With Afinitor recently approved in combination with hormone therapy and pursuing development in the adjuvant setting, and PD 0332991 now demonstrating highly meaningful clinical activity in ER+ patients, we are at the dawn of a new era in breast cancer treatment that could have significant impact on the future course of the disease.
By Stephanie Hawthorne, PhD, Director, Commercial Development, Kantar Health and Josh Garcia, Associate Consultant, Kantar Health