Approximately 3-7 percent of non-small cell lung cancer (NSCLC) patients have alterations to their anaplastic lymphoma kinase (ALK) gene, which serves as the oncogenic driver for their disease. For this patient subpopulation (termed ALK-positive), treatment with the tyrosine kinase inhibitor (TKI) crizotinib became the standard treatment since the FDA's approval for this indication in 2011. Unfortunately, NSCLC patients treated with this inhibitor almost always display disease progression, often with CNS-based metastases, as a result of the presence of mutants that confer acquired resistance. As a result, next-generation TKIs have been developed to address this shortcoming of crizotinib.
One such compound developed to address this need is ceritinib, an orally-bioavailable small-molecule next-generation ALK-TKI that showed 20-fold improvement over crizotinib in enzyme-binding assays. Additionally, this compound showed in vivo efficacy in xenograft models against both crizotinib-resistant and crizotinib-susceptible ALK-positive NSCLC cell lines. Largely based on the results from the ASCEND-1 clinical trial (NCT01283516), the FDA granted accelerated approval to ceritinib in April 2014 for the treatment of ALK-positive NSCLC patients who were intolerant to or had undergone disease progression while on crizotinib. In ASCEND-4 (NCT01828099), Jean Charles Soria, MD, Department of Cancer Medicine, Institut Gustave Roussy, and colleagues, evaluated the use of ceritinib versus platinum-based chemotherapy with pemetrexed followed by pemetrexed maintenance in untreated stage IIIB/IV ALK-positive NSCLC patients with non-squamous histology.
Ceritinib-A Second Generation ALK Inhibitor
Over the course of their treatment, almost all ALK-positive NSCLC patients receiving crizotinib therapy will develop disease resistant to that drug. In approximately one-third of these patients, this acquired resistance arises from the emergence of additional mutations in the ALK gene. Two of the most frequently encountered of these resistant secondary mutations are G1269A and L1196M. Other mutations that have been identified in patients with crizotinib-resistant disease include C1156Y, G1202R, L1152R, S1206Y, and 1151Tins. Another third of the patients that develop crizotinib-resistant cancers are thought to be the result of bypass signaling tract activation (e.g., epidermal growth factor receptor (EGFR), proto-oncogene c-KIT, PI3K activation). For the remaining third, the mechanisms of their crizotinib resistance are not fully understood.
To address the issue of crizotinib-resistant ALK mutations, a number of second-generation ALK inhibitors (ALK-i) were developed. One of the more active of these compounds was ceritinib. A thorough report of the preclinical testing for ceritinib was presented by Jeffrey Engelman, MD, PhD, Massachusetts General Hospital, Harvard Medical School, Boston, and colleagues (Cancer Discov 2014;4(6):662-673).
Ceritinib is an ATP-competitive ALK TKI, as are most other compounds of that class. Additionally, this compound shows great selectivity specifically for the ALK enzyme. When tested in a cell proliferation assay against a panel of 16 different kinases, ALK was the only enzyme that showed inhibition below 100 nM. As a further test of the ceritinib's specificity, growth assays were performed with a number of different cell lines having different oncogenic drivers. While potency was noted against two lung cancer cell lines with ALK rearrangements, little effect was noted (i.e. GI50 values > 1 μM) against breast cancer or NSCLC lines having KRAS, PI3K, EGFR, or HER2 oncogenic drivers.
Ceritinib also displayed great potency, showing approximately 20-fold greater activity than crizotinib in enzymatic assays. To assess its efficacy against crizotinib-resistant mutations, ceritinib was evaluated in assays that utilized Ba/F3 murine cells, which had been genetically engineered to express wild type EML4-ALK or the aforementioned resistance-associated mutations. Results from these assays showed that this second generation ALK-TKI was effective against four of the resistant mutations: G1269A, I1171T, L1196M, and S1206Y. Interestingly, some mutations, including 1151T-ins, C1156Y, F1174C, G1202R, and L1152R also resulted in ceritinib-resistant cells. Although ceritinib resistance was noted with the preceding mutations, that compound still showed greater potency than crizotinib against those resistant mutations. The in vitro efficacy results were subsequently confirmed using several different in vivo tumor xenograft models.
Although ceritinib has displayed robust tumor responses in crizotinib-resistant patients, as with other targeted therapies, the emergence of resistance to that therapy has been noted clinically. As of that 2014 study, 11 different ceritinib-resistant cancers had been biopsied. In these resistant cancer samples, five contained either F1174 or G1202 site mutations. Interestingly, two of the cancer samples which came from the same patient had two different ceritinib-resistant mutations, highlighting the genetic heterogeneity for this disease that can exist even within the same patient.
Another clinical observation regarding ceritinib was that efficacy was noted in crizotinib-resistant tumors that did not harbor a resistance-conferring mutation. Rather surprisingly, cell lines derived from these patients displayed crizotinib susceptibility in vitro, showing that despite the lack of in vivo activity the cells did have ALK sensitivity. The authors speculate that this observation may be due to the presence of sub-therapeutic doses of crizotinib in vivo, permitting the cancer cells to survive with moderate bypass track activation (e.g., EGFR, cKIT).
The ASCEND4 clinical trial was a randomized, open-label phase III study which evaluated the use of ceritinib vs. platinum-based chemotherapies in treatment-naïve ALK-rearranged non-squamous NSCLC patients. This large international study included patients from 134 different centers in 28 countries. Patients were randomized in a roughly 1:1 ratio to receive 750 mg ceritinib, p.o., q.d. or platinum-based chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5-6 plus pemetrexed 500 mg/m2, Q3W, four cycles) plus maintenance pemetrexed (500 mg/m2), Q3W.
Among the key inclusion criteria were: age (18 years or more); cytologically or histologically confirmed non-squamous NSCLC with confirmed ALK rearrangement (immunohistochemically (IHC) confirmed); untreated with any systemic cancer therapy (adjuvant or neoadjuvant therapy was allowed if relapse occurred more than 12 months after end of treatment); measurable disease using RECIST v.1.1 criteria; World Health Organization (WHO) performance status of zero, one, or twoF; asymptomatic or neurologically-stable (for 2 weeks or more) brain metastases.
In discussing the brain metastases inclusion, Soria had the following clarification “Patients with brain metastases were eligible if neurologically stable, symptomatic or not, and with or without previous brain radiation therapy. The incidence of patients with brain metastases in the ASCEND-4 study was high (32%) and most patients did not receive previous brain radiotherapy (59%). It may be important to highlight the difference in eligibility criteria for patients with baseline brain metastases in other ALK-inhibitor phase III studies to fully appreciate the intracranial activity of other compounds of this class: all had to be treated with brain radiotherapy and be neurologically stable in PROFILE 1014 (NCT01154140) and treated and asymptomatic in the J-ALEX Japanese study (JapicCTI-132316). In the ALEX study (NCT02075840), patients with brain metastases were eligible if asymptomatic.”
Among the key exclusion criteria were: sensitivity to any of the active or inactive ingredients of the investigational medications used; history of either interstitial pneumonitis (including clinically-significant radiation pneumonitis) or interstitial lung disease; history of carcinomatous meningitis; presence of another cancer or history of cancer other than NSCLC which had required therapy within the past 3 years (exceptions—completely resected carcinoma in situ of any type, completely resected basal cell or squamous cell skin cancers); clinically relevant uncontrolled heart disease or cardiac event within the past 6 months; gastrointestinal disease or impairment that would affect the patient's ability to properly absorb the orally-administered ceritinib; thoracic radiation therapy to lungs 4 weeks or less prior to study treatment initiation; not having recovered from previous radiotherapy-related toxicities; major surgery within 4 weeks or resection of brain metastases within 2 weeks of treatment initiation.
Patients were randomized in a 1:1 ratio to receive either 750 mg ceritinib daily (p.o., fasted dosing) or IV chemotherapy (75 mg/m2 cisplatin of AUC 5-6 carboplatin plus 500 mg/m2 pemetrexed) Q3W dosing. If patients in the chemotherapy arm underwent four cycles of chemotherapy without disease progression, they received maintenance pemetrexed (500 mg/m2, IV, Q3W). When asked about the patients in the chemotherapy arm that underwent disease progression, Soria replied “Crossover to ceritinib was allowed in the ASCEND-4 study for patients who had a RECIST documented progression as per investigator and confirmed by the Blinded Independent Review Committee. Eighty out of the 105 patients who discontinued chemotherapy received ceritinib in the crossover part of the study.”
Patients were stratified according to a number of different criteria, including: WHO performance status (0 vs. 1 or 2); prior adjuvant or neoadjuvant chemotherapy (yes vs. no); brain metastases as assessed by the investigator at screening (absent vs. present).
In summarizing the results for this trial, Soria noted, “The ASCEND-4 trial was the first randomized phase III study to demonstrate that a second generation ALK-i, ceritinib, significantly reduced the risk of disease worsening or death (progression-free survival, PFS) compared to frontline pemetrexed-platinum chemotherapy followed by pemetrexed maintenance in treatment-naïve ALK-positive advanced or metastatic NSCLC patients. The median PFS by a Blinded Independent Review Committee was unprecedented in that population and noted at 16.6 months (95% CI; 12.6-27.2 months) in the ceritinib group and 8.1 months (95% CI; 5.8-11.1 months) in the chemotherapy group for a hazard ratio (HR) of 0.55 (95% CI; 0.42 - 0.73; p < 0.00001). It is acknowledged that cross-trial comparison can have limitations. That being said, the ASCEND-4 results show that patients may potentially expect to have their disease controlled for a longer period if they are treated with ceritinib instead of crizotinib, the only ALK-i to be globally approved for the first line treatment of ALK-positive metastatic NSCLC to date.
The median PFS in the PROFILE-1014 study was 10.9 months (95% CI; 8.3 - 13.9 months) with crizotinib group, as compared with 7.0 months (95% CI; 6.8-8.2 months) among patients treated with pemetrexed-platinum chemotherapy without pemetrexed maintenance (Solomon et al 2015). Other second generation ALK-i are under evaluation. Results from the ALEX study, which is evaluating alectinib versus crizotinib in treatment-naïve ALK-positive NSCLC patients, have been recently announced to be statistically positive in favor of alectinib. The ALEX trial is of greater interest to the NSCLC community than the J-ALEX study, which is being conducted in only Japanese ALK-positive NSCLC patients, as the ALEX study is a global trial conducted across 161 sites in 31 countries.”
When discussing the brain metastases stratification, Soria noted “In a preplanned subgroup analysis, the median PFS in patients without evidence of brain metastases at baseline was even longer: 26.3 months (95% CI; 15.4-27.7 months) with ceritinib compared to 8.3 months (95% CI; 6.0-13.7 months) for chemotherapy. Ceritinib has demonstrated activity in patients with brain metastases. Despite the fact that ceritinib may be transported by P-glycoprotein (P-gp) efflux protein, we have observed evidence of high antitumor efficacy in patients with brain metastases treated in this study. In ASCEND-4, the intracranial activity observed in ceritinib patients with measurable brain metastases at baseline and at least one post-baseline assessment (as assessed by the blinded independent review board neurologist using a modified RECIST 1.1 allowing selection of up to five brain lesions as target) showed a high overall intracranial response rate of 72.7 percent, an intracranial clinical benefit rate of 86.4 percent at 24 weeks, and a median duration of intracranial response of 16.6 months (95% CI; 8.1 - not estimable). Based on these results, the FDA granted ceritinib Breakthrough Therapy Designation for the treatment of patients with brain metastases.”
Soria offered the following observations about the patient responses in this study “Responses with ceritinib were deep, rapid, and prolonged. The median time to response was 6.1 weeks (corresponding to the first tumor assessment, IQR 5.9-6.7 weeks, n=137) for ceritinib. The median duration of response was long, noted at 23.9 months (95% CI; 16.6 months-not estimable) in the ceritinib group. Investigator-reported overall response and duration of response were remarkably consistent and similar to those reported by the blinded independent review committee.”
Soria noted the following regarding the safety and tolerability for ceritinib in this study “The proportion of patients who had SAEs suspected to be study drug-related was similar in the ceritinib group and chemotherapy group (about 15%). The SAEs suspected to be study drug-related reported in ≥ 2 percent of patients in the ceritinib group were nausea (3.2%), vomiting (3.2%), AST (2.1%) and in the chemotherapy group were nausea (2.9%), and vomiting (2.3%). There were no drug-related SAEs with fatal outcome in the ceritinib group. The safety profile of ceritinib was manageable, although more challenging than that observed with crizotinib. Although dose reductions and interruptions were frequently required to manage safety events (mainly GI and liver enzyme AEs), the duration of treatment was long (66.4 weeks) and very few patients discontinued treatment as a result of these AEs.”
When asked how the patients' quality of life had been affected by the investigational medications in this study, Soria noted that “ceritinib significantly prolonged time to definitive deterioration versus chemotherapy for the composite endpoint of lung cancer-specific symptoms (pain, cough, and shortness of breath; LCSS, HR 0.61 [95% CI 0.41 – 0.90]; p = 0.0055, and QLQ-LC13, HR 0.48 [0.34-0.69]; p < 0.0001. As measured by LCSS and QLQ-LC13, the patient-reported outcomes in lung cancer-specific symptoms were significantly improved for ceritinib versus chemotherapy. All QLQ-LC-13 symptom scores improved significantly versus chemotherapy. In the QLQ-C30 instrument, most of the functional domains and symptom scales improved significantly with ceritinib versus chemotherapy. Two scales related to diarrhea as well as nausea and vomiting showed less favorable outcomes for ceritinib.”
At this point, Soria highlighted the effectiveness of other ALK-i's in treating brain metastases “Crizotinib's limited activity against brain metastases is known and well described in the literature (Costa et al. 2015) and may be related to its low cerebrospinal fluid to plasma ratio (Costa et al. 2011). Recent reports have indicated that alectinib exhibits high antitumor efficacy against brain metastases. This may be due to a high penetration in the brain as well due to a poor efflux from the brain. Alectinib might not be transported by P-glycoprotein (P-gp) efflux protein, a key protein for blood-brain barrier penetration (Kodama et al. 2014). In addition to alectinib, novel compounds, such as AP26113 and PF-06463922, have also been demonstrated to be effective for CNS lesions (Camidge et al. ASCO 2015, Shaw et al, ASCO 2015).”
When asked what he thought the most positive development was with regards to this study, Soria readily replied “ALK translocated patients have to be treated by an ALK-i in the frontline setting and not with chemotherapy. Ceritinib appears to be, along with crizotinib, another frontline option for patients with ALK-positive advanced or metastatic NSCLC. Another very important finding of this study is the observation that ceritinib has a high intracranial response in patients with brain metastases. About 60 percent of the patients with brain metastases did not receive brain radiation therapy prior to inclusion in this study.”
In discussing other clinical trials utilizing ceritinib, Soria said, “The only trial I am aware of is Study A2112, which is a multi-center, randomized open-label study to assess the systemic exposure, efficacy, and safety of 450 mg ceritinib taken with a low-fat meal and 600 mg ceritinib taken with a low-fat meal as compared with that of 750 mg ceritinib taken in the fasted state in adult patients with ALK rearranged (ALK-positive) metastatic NSCLC. Part one of Study A2112 intends to evaluate the single-dose and steady-state PK, the safety profile (including GI AEs), and the efficacy of 450 mg or 600 mg ceritinib taken daily with a low-fat meal as compared with that of 750 mg daily in the fasted state in both treatment-naive and pre-treated patients with ALK-positive NSCLC. Part two of the study intends to evaluate the efficacy of ceritinib across the three doses in treatment-naïve patients with ALK-positive NSCLC by IHC. The study is currently on-going and enrollment will continue for treatment-naïve patients (ALK-positive by IHC) with the purpose of evaluating efficacy of ceritinib in these patients (Part two of the study) (Dziadziuszko R et al. WCLC 2016).”
He further elaborated on the initial findings from that study, “The primary PK and preliminary safety results indicate that ceritinib 450 mg fed arm demonstrated improvement in GI tolerability while also maintaining comparable steady-state exposure to the approved recommended dose of ceritinib 750 mg fasted.”
Richard Simoneaux is a contributing writer.