Over the past several years the melanoma community has witnessed an explosion of new agents for the treatment of advanced melanoma with the approvals of Yervoy® (ipilimumab, Bristol-Myers Squibb), Zelboraf® (vemurafenib, Genentech/Roche/Daiichi Sankyo), Tafinlar® (dabrafenib, GlaxoSmithKline) and Mekinist® (trametinib, GlaxoSmithKline). While Zelboraf, Tafinlar and Mekinist are primarily used in patients harboring BRAF mutations, immunotherapy such as Yervoy offers a treatment option for those without the mutations or those who progressed on BRAF pathway-targeted therapy. Following the initial excitement surrounding Yervoy, other checkpoint inhibitors have entered the clinical pipeline, namely inhibitors of the Programmed Death-1 (PD-1) pathway.
The role of PD-1 in suppression of antitumor immunity was one of the hottest topics at the 2012 American Society of Clinical Oncology (ASCO) annual meeting. Excitement around this topic intensified at ASCO 2013, and the story continues to unfold in 2014. PD-1 is a key immune checkpoint receptor expressed on activated T-cells, and binding of PD-1 to its ligand (PD-L1) results in suppression of the immune response. While the PD-1 pathway normally plays a protective role by attenuating immune-mediated destruction of healthy tissue, the pathway can be exploited by cancer cells to protect themselves from tumor-specific T-cells. PD-L1, frequently expressed on the surface of tumor cells, binds PD-1 and suppresses the antitumor immune response. A number of agents that block the interaction between PD-1 and PD-L1, thereby activating the immune system against cancer cells, have recently entered into clinical development programs.
Past ASCO meetings have highlighted the promise of Bristol-Myers Squibb’s anti-PD-1 monoclonal antibody nivolumab, which generated impressive early clinical data suggesting improved overall response rate (ORR) with fewer toxicities when compared to historical data for Yervoy. However, at ASCO 2014 another anti-PD-1 monoclonal antibody, pembrolizumab (MK3475, Merck), took center stage with impressive Phase II data. This trial evaluated pembrolizumab in 411 patients (including Yervoy-naïve and Yervoy-treated) in melanoma expansion cohorts: 135 patients were enrolled into non-randomized cohorts (evaluating either q2w or q3w dosing schedules), and 276 patients were enrolled into randomized cohorts that compared 10 vs 2 mg/kg q3w schedules of pembrolizumab. Patients in the randomized cohorts had to have progressive disease following Yervoy and must have also received prior BRAF inhibitor if harboring BRAF mutation; there was no limit on the number of prior systemic therapies.
An independent radiologic review indicated an overall response rate (ORR) of 34% for all patients, including a 5% complete response (CR) rate. In Yervoy-naïve patients the ORR was 40% (8% CR); in Yervoy-treated patients the ORR was slightly inferior at 28% (2% CR). Subgroup analysis suggested a numerical trend toward higher ORR for the 10 mg/kg q2w dosing schedule; however, prospective randomized testing of 2 mg/kg q3w versus 10 mg/kg q3w (n=276) and 10 mg/kg q3w versus 10 mg/kg q2w (n=244; not reported) did not suggest superiority of any one dose regimen. Median response duration was not yet reached, and 88% of responses were ongoing at the time of reporting (range 6+ to 76+ weeks). The median progression-free survival (PFS) assessed by independent central review was 5.5 months for all patients, 5.6 months for Yervoy-naïve patients and 5.4 months for Yervoy-treated patients. Median overall survival (OS) was not yet reached, but at 12 months OS rate was 69% (74% for Yervoy-naïve and 65% for Yervoy-treated) and at 18 months OS rate dropped to 62%.
Most common drug-related adverse events (AEs) (any Grade; Grade 3/4) included fatigue (36%; 2%), rash (20%; <1%) and pruritus (24%; <1%). The incidence of drug-related Grade 3+ AEs was 12%, treatment-related toxicity leading to discontinuation occurred in 4% of patients, and there were no treatment-related deaths. Immune-mediated AEs (any grade; Grade 3/4) included hypothyroidism (8%; <1%), hyperthyroidism (1%; <1%), pneumonitis (3%; <1%), colitis (<1%, <1%) and hepatitis (<1%, <1%). Other potentially immune-mediated toxicities reported in less than 1% of patients included nephritis, hypophysitis and uveitis.
Nivolumab (with or without Yervoy) currently represents the strongest competitor to pembrolizumab. As Bristol-Myers Squibb initiated Phase III trials for nivolumab in December 2012 (relapsed melanoma) and January 2013 (first-line melanoma), it appeared that this agent would be the first to market. However, Merck announced in January 2014 that they filed a rolling submission for pembrolizumab in Yervoy-treated patients based on the results of the Phase II trial. The U.S. Food and Drug Administration (FDA) awarded pembrolizumab a Breakthrough Therapy designation in April 2013 and assigned a priority regulatory review with a decision date expected in the fourth quarter of 2014.
Although Merck’s submission might allow pembrolizumab to beat nivolumab to market in the relapsed/refractory setting, nivolumab still might ultimately prevail as it is being examined in two Phase III trials in newly diagnosed and relapsed/refractory settings. If one or both of these trials are successful, nivolumab could enjoy strong utilization in frontline and, as a consequence, keep pembrolizumab confined to later lines of therapy. Recognizing the drawbacks of potential confinement to later lines of therapy, Merck decided to challenge Yervoy by initiating a Phase III trial (NCT01866319) in September 2013 that will evaluate two dosing schedules of pembrolizumab (10 mg IV, either once every two weeks or once every three weeks) versus Yervoy in 645 Yervoy-naïve patients with unresectable or metastatic melanoma. This study includes patients who will receive first- or second-line treatment, with PFS and OS as co-primary endpoints. While going head-to-head with Yervoy is a good strategy, the combination trial of nivolumab and Yervoy currently poses the main threat for pembrolizumab. Data reported at ASCO 2014 showed an unprecedented two-year survival rate of 79% for the combination (as well as 43% ORR with 17% CR), which appears superior to pembrolizumab.1 However, just like the BRAF/MEK competition, subtle differences in efficacy and especially toxicity may dictate product uptake and the combination of nivolumab and Yervoy is certainly not without its share of higher incidence of Grade 3+ toxicities. The fight for the PD-1 space has begun, and it will be interesting to watch how the results play out for both nivolumab (with or without Yervoy) and pembrolizumab.
By Tatiana Spicakova, Ph.D., Consultant, and Neesha Suvarna, Ph.D., Consultant, Kantar Health
To date, the field of myeloma therapy has been dominated by proteasome inhibitors and immunomodulators (IMiDs). The past two years had two new entrants into the relapsed/refractory setting: Kyprolis® (carfilzomib, Onyx/Amgen), a proteasome inhibitor that was approved in 2012, and Pomalyst® (pomalidomide, Celgene) a second-generation IMiD approved in 2013. Both agents were approved for patients that had received two prior therapies, including Velcade® (bortezomib, Millennium/Takeda) and an immunomodulator; in the case of Kyprolis the immunomodulator was either thalidomide or Revlimid® (Celgene). The future of myeloma seems promising, with multiple novel targeted therapies that are currently in development; one of these reported data at ASCO 2014.
Panobinostat (LBH589) is a novel, multitargeted pan-deacetylase inhibitor developed by Novartis. In a Phase Ib trial, panobinostat in combination with Velcade plus dexamethasone (Veldex) was well-tolerated and achieved a 62% clinical benefit rate (six PR and two MR) in patients who were refractory to prior Velcade-based therapy. This formed the basis of a randomized Phase III trial (PANORAMA-1; NCT01023308) that evaluated panobinostat plus VelDex versus placebo plus VelDex in 768 previously treated patients with relapsed/refractory multiple myeloma. The trial was designed in two parts and conducted in 215 centers across 35 countries (including Europe and Asia). In treatment phase 1 (TP1), patients received oral panobinostat at 20 mg or placebo three times a week in combination with Velcade at 1.3 mg/m2 on Days 1 and 4 and oral dexamethasone at 20 mg on Days 1-2 and Days 4-5 each week, in a “two-week-on/one-week-off” schedule. Patients who achieved response in TP1 had the option to proceed to treatment phase 2 (TP2), whereby the panobinostat schedule was maintained but Velcade and dexamethasone administration was reduced to once per weekly cycle. The primary endpoint was progression-free survival (PFS), with response assessed by modified European group for blood and marrow transplantation (EBMT) score. Other endpoints included overall survival (OS), overall response rate (ORR), complete response/near complete response rate (CR/nCR) rate, duration of response (DOR), time to progression (TTP) and safety.
Eligible patients were randomized to the panobinostat/VelDex arm (n=387) or the VelDex-alone arm (n=381). The trial accrued patients who had relapsed on prior therapies, and the majority of patients had received prior Velcade (43.7% in panobinostat/VelDex arm versus 42.3% in VelDex arm). About one-quarter of the patients in each arm had received prior Velcade and IMiD (24.3% in panobinostat/VelDex arm versus 26% in VelDex arm). The trial met its primary endpoint and demonstrated a 3.9-month PFS improvement with panobinostat/VelDex compared to VelDex alone (12 months versus 8.1 months; p<0.0001; HR 0.63, 95% CI: 0.52-0.76). Subgroup analysis also demonstrated that the efficacy was better in patients who had received prior Velcade regimens (almost 40% of the patients). Numerical improvements in ORR were observed in the panobinostat/VelDex arm (60.7%) compared to the VelDex arm (54.6%); however, this trend did not approach significance. At the interim analysis for OS (134 events), there was a trend to OS benefit, but no significance was reached (mOS was 33.64 months in panobinostat/VelDex arm versus 30.39 months in VelDex arm); full survival analyses are expected after 415 events are reached. Significant improvements were also observed in CR/nCR rate in the panobinostat/VelDex arm compared to the VelDex arm (27.6% versus 15.7%; p=0.00006). The panobinostat/VelDex arm showed about a three-month improvement in mDOR (13.1 versus 10.9 months) and TTP (12.7 months versus 8.5 months).
Of concern is the toxicity profile observed with panobinostat plus VelDex. Nearly 67.4% of patients receiving panobinostat/VelDex had Grade 3-4 thrombocytopenia compared to 31.4% in the VelDex-alone arm. In addition, Grade 3-4 diarrhea and fatigue were high in panobinostat compared to the VelDex arm (diarrhea: 25.5% versus 8%; fatigue: 23.9% versus 11.9%). Treatment-related deaths were also higher in the panobinostat/Veldex combination (2.9%) compared to the VelDex arm (1.9%).
According to Kantar Health surveys, physicians prefer the first-generation proteasome inhibitors (Thalidomide and Velcade) and IMiD (Revlimid) in the first- or second-line setting, whereas the second-generation proteasome inhibitors and IMiDs are preferred in the third-line setting. The second-line setting has no established standard of care, so it will be interesting to see how panobinostat will be positioned. Cross-trial comparison of these three agents suggests that panobinostat plus VelDex has better efficacy compared with Pomalyst or Kyprolis. However, it is important to note that the efficacy in the table below compares Kyprolis monotherapy or Pomalyst/Dex to three-drug combination. It is also equally important to note that the trials for Pomalyst and Kyprolis enrolled patients who had received three or more prior lines of therapy, unlike the panobinostat trial that primarily accrued patients receiving only one prior line of therapy.
Table 1: Cross-trial comparison of the efficacy of panobinostat/VelDex versus Pomalyst or Kyprolis in relapsed/refractory myeloma patients
Another point that was noted by the discussant for the Panorama presentation was that it included a large percentage of patients who had received prior Velcade therapy, and a subgroup analysis noted that efficacy was better in prior Velcade-treated patients in the panobinostat arm compared with the control arm. This may contrast with the other agents that did not note such differential efficacy benefit.
The second-line setting is heavily contested with both Kyprolis and Pomalyst in pivotal trials that would support their adoption into the second-line setting if they were positive. Also under investigation are two unique targets: elotuzumab (CS-1 antibody, Abbvie/BMS/Ono) and daratumumab (CD38 antibody, Genmab, J&J). More immediately, Kyprolis is challenging VelDex in second-line therapy with the pivotal trial ENDEAVOR that will compare Kyprolis plus Dex versus VelDex (endpoint PFS) and Pomalyst in combination with VelDex versus VelDex in OPTIMISMM trial. If they reach the PFS endpoint both trials will provide major competition to panobinostat based on their adoption and familiarity with physicians in the relapsed/refractory setting. The pivotal ELOQUENT-2 trial also will compare elotuzumab plus RevDex versus RevDex alone based on clinical activity demonstrated in Phase I/II trials. Daratumumab is still in early clinical development, and no pivotal trials have been initiated to date. Time will tell whether the novel mechanism of action provided by panobinostat will be enough to garner physician excitement and to overlook the toxicity of this agent in relapsed/refractory multiple myeloma patients.
By Len Kusdra, Ph.D., Analyst, and Neesha Suvarna, Ph.D., Consultant, Kantar Health
Both Avastin® (bevacizumab, Genentech/Roche/Chugai) and Erbitux® (cetuximab, Bristol -Myers Squibb/Eli Lilly/Merck KGaA) are approved for the treatment of first-line metastatic colorectal cancer (mCRC) and have demonstrated progression-free survival (PFS) and overall survival (OS) benefits when added to standard chemotherapy in these patients. Avastin is approved for use in all first-line patients, while Erbitux is approved for use only in the subgroup of patients with wildtype KRAS. As with all therapies that exist in the same indication, physicians are left wondering how best to incorporate these agents into their practices. As multiple Phase III trials showed combining these two agents are not effective at best (and harmful in the extreme), two trials set about to understand whether one regimen is superior as an initial treatment option.
At the 2013 ASCO annual meeting, the data from one of these trials, FIRE-3, were presented.1FIRE-3 was a German trial designed to evaluate FOLFIRI plus either Erbitux or Avastin (at 5 mg/kg every two weeks) as first-line therapy; it was amended in 2008 to include only KRAS wildtype patients. The data suggested a non-significant benefit compared to Avastin for overall response rate, which was the primary endpoint (62% versus 58%, p=0.183). Moreover, a PFS benefit was not observed (HR 1.06, p=1.06); however, Erbitux was associated with a significant 3.7-month OS benefit compared to Avastin (HR 0.77, p=0.017). The Kaplan-Meier OS curves were especially intriguing, as the curves for each arm began to separate between 18 and 24 months, well after the 10-month PFS median, and the curves continued to separate past the median OS, where the superiority of Erbitux becomes far more pronounced and is evidently durable.
The conflicting data found in FIRE-3 begged for a repeat, and CALGB 80405, which was presented in the ASCO 2014 plenary session,2 has been highly anticipated for this reason. CALGB 80405 evaluated the addition of Erbitux or Avastin to physician’s choice of first-line chemotherapy (FOLFIRI or FOLFOX). When initiated in 2004, the trial enrolled all patients, as well as recruiting patients onto a third arm of Avastin plus Erbitux and chemotherapy. The trial was amended in 2009 to include only KRAS wildtype patients and halt recruitment to the arm with both Erbitux and Avastin. Ultimately, the trial enrolled 1,137 patients, and the primary endpoint was OS.
CALGB 80405 failed to show that either Erbitux or Avastin was associated with improved OS, as the Kaplan-Meier curves were essentially superimposable (median OS: 29.9 months for Erbitux versus 29.0 months for Avastin, HR 0.925, p=0.34). The curves for PFS were also essentially superimposable (median PFS: 10.8 months versus 10.4 months, HR 1.04, p=0.55). Subgroup analyses of patients treated with FOLFOX, which accounted for 73% of the patients enrolled in the trial, also showed no benefit for either drug (HR 0.9, p=0.09). Other data, including response rates, still need to be collected.
The “take-home” message is that efficacy differences are, for now, unlikely to drive the decision when choosing between these two agents for first-line mCRC therapy. Perhaps differences will emerge when evaluating secondary endpoints such as complete response rates, broader RAS mutant populations, or ability to resect patients to a disease-free state. For now, though, the choice of first-line therapy for mCRC patients is likely to be driven largely by the patient’s preference regarding potential side effects. The toxicity profiles were as expected for these agents, with the incidence of Grade 3-4 rash (7% versus 0%) and diarrhea (11% versus 8%) increased in the Erbitux arm, and the incidence of Grade 3-4 hypertension (1% versus 7%) and gastrointestinal events (0.5% versus 2%) increased in the Avastin arm. Updated DSQL skin satisfaction patient-reported survey data confirmed that skin rash was a significant concern for these patients (p<0.0001); however, this concern did not get reflected into results for the EORTC Global quality of life survey data (p=0.0546). The presenter, Dr. Venook, stated his belief that this may be because patients who get a rash feel “that the drug is working.”
In the absence of a confirmed efficacy benefit, cost could be another differentiator. In the post-plenary session, Dr. Saltz noted that the cost of Avastin per month is about half the cost of Erbitux per month (he referred to prices of $5,000 per month for Avastin and $10,000 per month for Erbitux).
Dr. Venook did not make an attempt to explain the discrepancy between the CALGB study and FIRE-3. The discussant (Dr. Tabernero) also did not do attempt to explain this. However, he did present updated FIRE-3 data, that indicated that use of an expanded RAS population (e.g., all RAS proteins are wildtype, not just the KRAS exon 2 as originally indicated) resulted in an improvement in the hazard ratio for both PFS (from 1.06 to 0.93) and OS (from 0.77 to 0.7). Dr. Tabernero suggested that this might result in CALGB 80405 finding a patient population in which Erbitux will show an OS advantage. Kantar Health is more skeptical of this claim, since it would be unlikely to shift the hazard ratios enough to be significant.
In a sense, CALGB 80405 provided a more definitive result than FIRE-3. The results lend themselves to a continuation of the current treatment plan. In the United States, Avastin is already outpacing Erbitux, being used in the majority of first-line KRAS wildtype patients, while in Europe Erbitux has a slight lead over Avastin.3 Given the clear results of CALGB 80405 and the apparently conflicted results of FIRE-3, global treatment patterns are unlikely to change: Tie goes to the runner!
By Arnold DuBell, Ph.D., Consultant, and Stephanie Hawthorne, Ph.D., Senior Director, Kantar Health
 Venook, LBA3, ASCO 2014
 Kantar Health, CancerMPact® Treatment Architecture United States and Western Europe, accessed June 1, 2014.