Can second-generation ALK inhibitors outshine Xalkori?
| Jun 3, 2013
Co-authored by Tatiana Spicakova, PhD, Consultant
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