In an effort to provide you with timely market feedback from ASCO 2013, OBR and MDoutlook are pleased to share results from MDoutlook’s first OncoPoll™ from the meeting exploring Thyroid cancer.
Stay tuned to our blog in the coming weeks as we publish more survey results in other tumor types as well.
Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age of diagnosis at 71 in the United States and nearly 40% of patients are older than 75 at the time of diagnosis1. Standard treatment for “fit” patients is aggressive chemotherapy, but existing co-morbidities in elderly patients often precludes the use of these highly toxic regimens. Limited treatment options exist for these patients and the most common choices include chlorambucil and Rituxan® (rituximab, Genentech/Roche) – alone or in combination. More recently the combination of Rituxan with Treanda® (bendamustine, Teva) has emerged as a common option in the U.S., although it is not approved for this setting. With few treatment options, there has been a rapid increase in the number of novel agents entering development for CLL in elderly newly-diagnosed patients as a niche target population. Phase III trials are ongoing for Arzerra® (ofatumumab, GlaxoSmithKline), ibrutinib (BTK inhibitor, Pharmacyclics/Johnson & Johnson), obinutuzumab (anti-CD20 monoclonal antibody, Genentech/Roche) and Revlimid® (lenalidomide, Celgene). The first of these agents to report pivotal results is obinutuzumab, which were presented at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in an oral session on June 42.
The Phase III CLL11 trial (NCT01010061) was a three-arm study that randomized 589 newly-diagnosed “unfit” patients to treatment with chlorambucil alone, chlorambucil plus obinutuzumab, or chlorambucil plus Rituxan. The definition of “unfit” in this trial wasn’t based on patient age, but was defined by the level of co-morbidities; patients were included if their total Cumulative Illness Rating Scale (CIRS) score was >6 and/or creatinine clearance <70 ml/min. The first stage of this trial is meant to compare the efficacies of each combination arm with the chlorambucil monotherapy arm; the second-stage (for which an additional 190 patients were enrolled) is meant to compare the efficacies of the two combination arms, and was designed to show superiority of obinutuzumab over Rituxan. The results presented at ASCO 2013 were for Stage I, and we will have to wait until later this year for the results of Stage II.
The results presented today showed clear and robust activity for obinutuzumab in combination with chlorambucil compared to chlorambucil alone, with improvements in complete response (CR) rate, overall response rate (ORR), and a high rate of minimal residual disease (MRD)-negativity (see Table 1). Progression-free survival (PFS; the primary endpoint) was significantly improved, with an 86% reduction in the risk of progression or death and a 23 month median PFS. The level of benefit was very impressive, although perhaps not surprising since chlorambucil is not a very active agent. Rituxan plus chlorambucil also showed a strong level of benefit compared to chlorambucil alone, with improvements in ORR and a 68% reduction in the risk of progression or death and a 16.7 month median PFS. Rituxan plus chlorambucil produced a modest CR rate and few patients were MRD-negative. In both combination arms, there was an increase in grade 3/4 neutropenia and infusion-related reactions, with rates appearing to be higher in the obinutuzumab arm; thrombocytopenia was also increased only in the obinutuzumab arm, and slightly more patients in this arm withdrew from the study due to adverse events. While these adverse events are of course concerning, the large magnitude of efficacy benefit means that these toxicities are unlikely to sway physicians away from use of the drug, especially since they are easily monitored and resolvable.
The results from this Stage I of the trial will initiate regulatory filings for obinutuzumab in newly-diagnosed CLL patients with comorbidities that make them unfit for standard chemotherapy. These Stage I results were extremely positive and certainly support approval, but the real story (and the one everyone is waiting for) is the result of Stage II – how does obinutuzumab compare statistically to Rituxan? We have to wait a while longer for those official results, but it is certainly tempting to compare by eye the results for both arms in Stage I. The three biggest measures that stand out are the CR rate, the number of patients who achieve negative MRD (in both the peripheral blood and the marrow), and PFS. All of these measures appear to strongly favor obinutuzumab. CR and MRD-negativity speak to the depth of response that is achieved, and previous data has established that MRD can independently predict for PFS and OS in CLL3. When we look at the PFS results as presented (which were based on investigator assessment), there is a 7.3 month difference at the median and a 21% difference in one-year PFS in favor of the obinutuzumab arm, although the Hazard Ratios suggest a slightly more moderate level of benefit (again, we have to stress that this type of comparison bears no statistical meaning). Somewhat concerning is the high number of censored patients “above the median” when we view the Kaplan-Meier curve for obinutuzumab; this leaves potential for the curve to change dramatically with further follow-up. Assessment of PFS by independent review was not presented, but noted to be “consistent” with the investigator assessment, although it would have been nice to see those curves and judge for ourselves. Nevertheless, the data certainly suggests that the results of Stage II have a good chance of proving obinutuzumab to be superior to Rituxan. This would be the first step of many to improve upon the efficacy of Rituxan and ultimately displace it as the standard of care in B-cell malignancies (conveniently coinciding with rituximab patent expiration).
Within chemo-ineligible/“unfit” newly-diagnosed CLL, where will obinutuzumab fit? As mentioned, development in this indication is crowded with promising new agents all seeking to transform the treatment paradigm. GlaxoSmithKline recently announced that the COMPLEMENT-1 trial of Arzerra plus chlorambucil versus chlorambucil monotherapy in previously untreated chemo-ineligible CLL patients met its primary endpoint by extending PFS from 13.1 months to 22.4 months (HR 0.57), which looks similar to the obinutuzumab results at the median, although the Hazard Ratios favor obinutuzumab (cross-trial comparisons with caveats). With this data, CLL will soon have three anti-CD20 antibodies to choose from. In addition, dinaciclib, ibrutinib and Revlimid are all seeking approval in this same patient population, and based on early trial results all have a good chance at being successful. A natural inclination would be to combine these agents with an anti-CD20 antibody, or potentially with each other, as well as bring these agents into the broader CLL population. CLL is very likely to be transformed in the next few years, with potentially more options than physicians know what to do with. We’ve encountered this problem before (renal cell carcinoma (RCC) comes to mind), but unlike RCC the influx of new agents in CLL have a large variety of mechanisms of action – an exciting turn of events!
By Neesha Suvarna, PhD, Consultant, Kantar Health and Stephanie Hawthorne, PhD, Director, Kantar Health
Anaplastic lymphoma kinase (ALK) was originally discovered as a fusion oncogene with nucleophosmin (NPM) in a subset of anaplastic large cell lymphomas (ALCL). When fused to other proteins, ALK becomes constitutively active, leading to increased catalytic kinase activity and oncogenic function. It was not until 2007 that ALK became a hot target in non-small cell lung cancer (NSCLC) when a novel fusion was discovered between ALK and the echinoderm microtubule-associated protein-like 4 (EML4) gene. Although other ALK fusion variants have been described, EML4-ALK is the most common variant expressed in approximately 5% of the NSCLC population. Similarly to EGFR mutations in NSCLC, ALK rearrangements have been associated with certain features such as absence of smoking history, adenocarcinoma histology and absence of other oncogenic drivers.
Xalkori® (crizotinib, Pfizer) is the first ALK inhibitor approved in ALK+ NSCLC patients. Results from a large Phase I trial (Camidge, Abstract 2501, ASCO 2011) showed an overall response rate (ORR) of 60.8% in 143 evaluable patients, with a median progression-free survival (PFS) of 9.7 months and median duration of response of 49.1 weeks. Results from the Phase III PROFILE 1007 trial confirmed Xalkori’s efficacy as second-line therapy in 347 ALK+ NSCLC patients by improving PFS from 3 to 7.7 months compared with chemotherapy. Not surprisingly, Pfizer also initiated a Phase III trial (PROFILE 1014) in the front-line ALK+ setting in which Xalkori monotherapy is compared to Alimta/platinum.
Xalkori has certainly proved itself as a very efficacious drug by achieving spectacular responses in ALK+ patients which led the U.S. regulatory agency to grant a generous broad label to Xalkori (including first-line) despite the absence of randomized data. However, the tremendous excitement and enthusiasm that Xalkori sparked is tempered by the reality that most patients will eventually relapse. Therefore, there has been a great interest in understanding the mechanisms of resistance to ALK inhibitors in order to develop new therapeutic strategies.
Data so far indicate that approximately one-third of Xalkori relapsed patients acquire secondary resistance mutations in the ALK tyrosine kinase domain (with L1196M representing the gatekeeper mutation, although it is not the only resistant mutation identified so far). Since these tumors are still addicted to ALK, second generation ALK inhibitors could become a new effective treatment option for these patients. Two such drugs in clinical development are AP26113 (ARIAD Pharmaceuticals) and LDK378 (Novartis).
During the 2013 American Society of Clinical Oncology (ASCO) annual meeting poster discussion session on June 2, results were presented from a Phase I/II trial that evaluated AP26113 in patients with advanced malignancies (Camidge, Abstract 8031). AP26113 not only inhibits ALK (including the gatekeeper mutation L1196M) but also has activity against T790M EGFR (the notorious resistance mutation for EGFR inhibitors). In this trial, doses were escalated using the 3+3 design from 30 mg once daily (QD) to 300 mg QD. The maximum tolerated dose (MTD) was not determined but based on the data, the recommended Phase 2 dose was 180 mg. In 55 evaluable patients, the most common toxicities included fatigue (40% all grades; 5% Grade 3/4), nausea (36% all grades; 0% Grade 3/4) and diarrhea (33% all grades; 4% Grade 3/4). Of note, no rash – a classic EGFR inhibitor toxicity was observed. Of 16 patients who received prior Xalkori therapy (but no other ALK inhibitor), 12 (75%) responded. Of three patients who received prior Xalkori and LDK378, one remained on study with stable disease, one discontinued due to progressive disease and one discontinued prior to follow-up scan. In patients who achieved a response, durations ranged from 15+ to 40+ weeks. Moreover, four of five ALK+ patients with untreated or progressing central nervous system (CNS) lesions at baseline showed radiographic improvements, including one patient resistant to Xalkori and LDK378. Based on these results, a pivotal Phase II trial will be initiated in patients with ALK+ NSCLC resistant to Xalkori but the details regarding the trial design have not yet been disclosed.
During the clinical science symposium session on June 3, data were presented for LDK378 from a Phase I study in patients with advanced ALK+ malignancies (Shaw, Abstract 8010). In this trial, 130 patients were enrolled, including 123 patients with ALK+ NSCLC. The drug was administered at escalating doses from 50 to 750 mg QD. The MTD was established at 750 mg QD and 71 patients were treated in an expanded cohort at the MTD, which included ALK+ lung cancer and non-lung ALK+ tumors. Of 130 patients, 122 (94%) had NSCLC. Among the 122 NSCLC patients, 82 (63%) received prior Xalkori and 40 (31%) were Xalkori-naïve. In 114 evaluable NSCLC patients across all doses, the ORR was achieved in 66 (58%) patients: 65 (57%) with confirmed partial response (PR) and 1 (1%) with confirmed complete response (CR). In 79 Xalkori-resistant patients, ORR was achieved in 45 (57%) patients: 44 (56%) PR and 1 (1%) CR. In 35 Xalkori-naïve patients, ORR was achieved in 21 (60%) patients (all PRs). Similar efficacy was observed in the MTD cohort (59% ORR in Xalkori-resistant patients and 62% in Xalkori-naïve patients). Median PFS (n=114) was 8.6 months and median duration of response (n=66) was 8.2 months. Responses were observed in patients with different Xalkori resistance mutations as well as in patients without detectable mutation. As was observed with AP26113, responses were also seen in patients with CNS metastases. In terms of toxicity, the most common toxicities (all grades; n=130) included nausea (73%), diarrhea (72%), vomiting (58%), and fatigue (41%). The most common Grade 3/4 toxicities (n=130) included ALT elevation (19%), diarrhea (8%), and AST elevation (10%). Based on the results, Novartis plans to initiate two Phase III trials in ALK+ NSCLC in June 2013. The first trial (NCT01828112) will evaluate LDK378 versus chemotherapy in ALK+ patients who were previously treated with chemotherapy and Xalkori. The second trial will evaluate LDK378 versus chemotherapy in previously untreated ALK+ patients (NCT01828099).
One of the questions surrounding the development of multiple second-generation ALK inhibitors is how exactly will they fit into the treatment landscape of ALK+ NSCLC and should Pfizer be concerned? It is clear that both Ariad and Novartis have plans to position their drugs in the Xalkori-resistant patient population – an area of high unmet of need in which securing approval should be relatively straight forward given the activity of both drugs. Novartis chose to be more aggressive with their development plans and also plans to evaluate LDK378 in the ALK+ frontline setting in a Phase III trial. Novartis did not choose to challenge Xalkori in a head-to-head trial but uses chemotherapy as a comparator instead. It is difficult to evaluate whether LDK378 can outshine the activity of Xalkori in the frontline setting in the absence of a head-to-head trial but given current available data, both agents seem fairly similar in terms of response rates. If that holds up in the Phase III trial, physicians may not choose to adopt LDK378 as frontline regimen but rather utilize it once patients progress on Xalkori since it is active in relapsing patients and these patients currently don’t have any other options besides chemotherapy. There is one agent, however, that might stand a chance to outshine Xalkori in the frontline – CH5424802 (RO5424802, Chugai/Roche).
Updated Phase I/II results for CH5424802 were presented on June 2 during the poster discussion session (Nakagawa, Abstract 8033). In 46 Xalkori-naïve Japanese patients, CH5424802 achieved an unprecedented ORR of 93.5% and median duration of response exceeding 14 months – to our knowledge, this magnitude of benefit far exceeds that observed for Xalkori or the other second-generation ALK inhibitors. If the magnitude of ORR and duration of response benefit holds up for CH5424802 and the drug eventually becomes approved, it certainly has the potential to outshine Xalkori in the frontline. According to the poster presenter, the design for Phase III trial is currently under discussion but given the data, one might expect a trial in the frontline setting.
Xalkori has enjoyed the spotlight in ALK+ NSCLC for almost two years now but that may soon change with the influx of second-generation ALK inhibitors. The second generation inhibitors are typically more potent than Xalkori (see table above) and also have activity against the gatekeeper L1196M mutation (as well as other resistance mutations). While they are certainly poised to dominate in the Xalkori-resistant setting, Pfizer should be on the lookout for maturing data in the frontline setting.
1 Puig de la Bellacasa, Transl Lung Cancer Res, 2013
2 Camidge, Abstract 2501, ASCO 2011
3 Camidge, Abstract 8031, ASCO 2013
4 Shaw, Abstract , ASCO 2013
5 Nakagawa, Abstract 8033, ASCO 2013
By Neesha Suvarna, PhD, Consultant, Kantar Health and Tatiana Spicakova, PhD, Consultant, Kantar Health
Glioblastoma has an angiogenic component, as the disease manifests itself as a focal lesion with central necrosis surrounded by an angiogenic tumor rim1. Genentech and Roche took advantage of this with the data from the phase II BRAIN study (AVF3708g), which suggested that single-agent Avastin® (bevacizumab) was active, with a six-month PFS rate of 42.6% and was slightly higher (50.3%) in combination with irinotecan2. Based on this data, the U.S. FDA conditionally approved the use of Avastin for glioblastoma patients with progressive disease.
As a condition to convert this approval to a full approval, the companies agreed to perform a confirmatory Phase III trial; moreover, the European Medicines Agency (EMA) chose not to approve Avastin based solely on the BRAIN study results, and so any European approval for Avastin in glioblastoma also relies on the results of Phase III studies. Initial results of the Roche-sponsored AVAglio (BO21990) study were presented in 2012 at the Annual Society for Neuro-Oncology meeting, which indicated that the addition of Avastin to standard therapy (temozolomide plus radiotherapy followed by temozolomide maintenance) significantly improved progression-free survival (mPFS: 10.6 months versus 6.2 months, HR 0.64, p<0.0001). However, this was coupled with news that the co-primary endpoint of overall survival (OS) had not reached significance (HR 0.89, p=0.2135)3. Anticipation was high at the 2013 American Society of Clinical Oncology (ASCO) annual meeting amongst neuro-oncologists for several reasons: final OS data were presented for AVAglio, and the initial data were presented for a second phase III trial sponsored by the Radiation Therapy Oncology Group (RTOG 0825) which also compared Avastin to standard therapy in newly-diagnosed glioblastoma patients. Both data may have muddied the picture more for Avastin in glioblastoma than it helped.
Dr. Wick presented the final AVAglio data (Abstract 2002), which confirmed that the addition of Avastin did not improve OS (mOS: 16.8 months versus 16.7 months, HR 0.88, p=0.0987). Moreover, Dr. Henricksson (Abstract 2005) presented further data that showed that patients treated with Avastin in AVAglio experienced improved quality of life as measured by five scales of the QLQ-C30 and BN20 survey instruments: global health status (HR 0.64, p<0.0001), physical functioning (HR 0.70, p<0.0001), social functioning (HR 0.63, p<0.0001), motor dysfunction (HR 0.67, p<0.0001), and communication deficit (HR 0.67, p<0.0001).
Confusing matters was RTOG 0825, which was presented at the plenary session (Gilbert, Abstract 1). The trial was designed similarly to AVAglio, in that newly-diagnosed patients were randomized to receive temozolomide-based radiotherapy with or without Avastin followed by maintenance therapy with either temozolomide or temozolomide plus Avastin. The discussant (Dr. Fine) noted that the two trials had similar distributions of patient characteristics such as performance status, resection type and MGMT methylation status. Unfortunately, the similarities end there. Although the addition of Avastin numerically improved PFS (mPFS: 10.7 months versus 7.3 months, HR 0.79, p=0.007), it did not meet the pre-specified threshold of a 30% reduction in the hazard of failure. Similar to AVAglio, Avastin did not meet its co-primary endpoint of OS (mOS: 15.7 months versus 16.1 months, HR 1.13, p=0.21)
Avastin administration was associated with an increase in several select Grade 3 or 4 adverse events: hypertension (4.6% versus 1.0%), deep-vein thrombosis/pulmonary embolism (9.9% versus 7.7%), wound issues (2.3% versus 1.0%), GI perforations (1.3% versus 0.7%), hemorrhage (1.3% versus 1.0%) and neutropenia (15.1% versus 7.3%).
Health-related quality of life (HRQoL) analyses were a secondary endpoint of RTOG 0825. Furthering the dissimilarity to AVAglio, Dr. Armstrong reported that Avastin was associated with declines in cognitive function (Interaction effect = 0.009), motor dysfunction (Interaction effect = 0.014), and communication deficits (Interaction effect = 0.003; Abstract 2003). Moreover, Dr. Wefel reported that Avastin was associated with greater rates of neurocognitive decline (CTB Composite, p=0.02; Abstract 2004). There are a variety of reasons for these differences as noted by the plenary session discussant, Dr. Fine, and included that these were subset analyses – neither trial had a full set of HRQoL data – and unspecified differences in how these data were analyzed.
Based on the combined data set from AVAglio and RTOG 0825, it is clear that Avastin has only a limited role for newly-diagnosed patients. Dr. Gilbert noted in a post-plenary discussion that there is “anecdotal” experience that Avastin may be effective in the small population of patients with high edema.
The question remains what might happen with the current U.S. FDA conditional approval for Avastin’s use in relapsed or refractory patients. At the post-plenary discussion, Drs. Gilbert and Fine noted that they use Avastin for their relapsed patients, and would probably continue to do so. Their stated rationale was that there are no approved agents other than Avastin for these patients for whom prospects were so dire. There are only two agents who have active Phase III trials, rindopepimut (Celldex Therapeutics) and DC-Vax-L® (Northwest Biotherapeutics). Avastin differs from other recently failed trials such as cilengitide’s (Merck KGaA) CENTRIC trial (Stupp, Abstract LBA2009) in that a PFS benefit has been seen.
The discussant to the RTOG 0825 data, Dr. Fine, provided a biological rationale for continuing to use Avastin in relapsed patients. As alluded above, there are two predominant growth patterns within glioblastoma: VEGF-driven and VEGF-independent parts of the tumor. These have histological components, as the VEGF-driven tissues are central masses while the VEGF-independent tissues appear as peripheral flares. Dr. Fine provided data that in newly-diagnosed GBM, the tumor lesions appear to be much less vascularized, which may explain the lack of efficacy of anti-angiogenic agents in this setting. Additionally, in patients treated with front-line Avastin, the VEGF-independent peripheral flares predominate, which would render any recurrences insensitive to angiogenic inhibition as well. In contrast, VEGF-driven central masses predominate more in patients who relapse after cytotoxic therapy, which may explain the sensitivity of these tumors to Avastin.
There is sure to be a high level of debate about the fate of Avastin in GBM, and Kantar Health believes that although the FDA will not entertain a new application for Avastin in newly-diagnosed patients, the agency might be willing to convert the conditional approval in relapsed patients to a full one, or at least maintain the accelerated approval. The PFS benefit seen in these two separate Phase III trials (albeit a non-significant trend in RTOG 0825), coupled with the long-term responders seen in the Phase II trials in recurrent patients may be sufficient evidence of activity for Avastin in the relapsed setting. In spite of the failure to reach the OS endpoint, the data do highlight that Avastin is still the most promising agent since the introduction of temozolomide in 2005. As Dr. Fine noted in his title of his discussion, “You knew it wasn’t going to be that easy.”
By Stephanie Hawthorne, Director, Kantar Health and Arnold DuBell, Associate Consultant, Kantar Health