Summary Background ALK fusion genes occur in a subset of non-small-cell lung cancers (NSCLCs). We assessed the tolerability and activity of crizotinib in patients with NSCLC who were prospectively ...identified to have an ALK fusion within the first-in-man phase 1 crizotinib study. Methods In this phase 1 study, patients with ALK -positive stage III or IV NSCLC received oral crizotinib 250 mg twice daily in 28-day cycles. Endpoints included tumour responses, duration of response, time to tumour response, progression-free survival (PFS), overall survival at 6 and 12 months, and determination of the safety and tolerability and characterisation of the plasma pharmacokinetic profile of crizotinib after oral administration. Responses were analysed in evaluable patients and PFS and safety were analysed in all patients. This study is registered with ClinicalTrials.gov , number NCT00585195. Findings Between Aug 27, 2008, and June 1, 2011, 149 ALK -positive patients were enrolled, 143 of whom were included in the response-evaluable population. 87 of 143 patients had an objective response (60·8%, 95% CI 52·3–68·9), including three complete responses and 84 partial responses. Median time to first documented objective response was 7·9 weeks (range 2·1–39·6) and median duration of response was 49·1 weeks (95% CI 39·3–75·4). The response rate seemed to be largely independent of age, sex, performance status, or line of treatment. Median PFS was 9·7 months (95% CI 7·7–12·8). Median overall survival data are not yet mature, but estimated overall survival at 6 and 12 months was 87·9% (95% CI 81·3–92·3) and 74·8% (66·4–81·5), respectively. 39 patients continued to receive crizotinib for more than 2 weeks after progression because of perceived ongoing clinical benefit from the drug (12 for at least 6 months from the time of their initial investigator-defined disease progression). Overall, 144 (97%) of 149 patients experienced treatment-related adverse events, which were mostly grade 1 or 2. The most common adverse events were visual effects, nausea, diarrhoea, constipation, vomiting, and peripheral oedema. The most common treatment-related grade 3 or 4 adverse events were neutropenia (n=9), raised alanine aminotransferase (n=6), hypophosphataemia (n=6), and lymphopenia (n=6). Interpretation Crizotinib is well tolerated with rapid, durable responses in patients with ALK -positive NSCLC. There seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed. Funding Pfizer.
Summary Background ALK gene rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). In a recent phase 1 clinical trial, the ALK tyrosine-kinase inhibitor (TKI) crizotinib ...showed marked antitumour activity in patients with advanced, ALK-positive NSCLC. To assess whether crizotinib affects overall survival in these patients, we did a retrospective study comparing survival outcomes in crizotinib-treated patients in the trial and crizotinib-naive controls screened during the same time period. Methods We examined overall survival in patients with advanced, ALK-positive NSCLC who enrolled in the phase 1 clinical trial of crizotinib, focusing on the cohort of 82 patients who had enrolled through Feb 10, 2010. For comparators, we identified 36 ALK-positive patients from trial sites who were not given crizotinib (ALK-positive controls), 67 patients without ALK rearrangement but positive for EGFR mutation, and 253 wild-type patients lacking either ALK rearrangement or EGFR mutation. To assess differences in overall survival, we assessed subsets of clinically comparable ALK-positive and ALK-negative patients. Findings Among 82 ALK-positive patients who were given crizotinib, median overall survival from initiation of crizotinib has not been reached (95% CI 17 months to not reached); 1-year overall survival was 74% (95% CI 63–82), and 2-year overall survival was 54% (40–66). Overall survival did not differ based on age, sex, smoking history, or ethnic origin. Survival in 30 ALK-positive patients who were given crizotinib in the second-line or third-line setting was significantly longer than in 23 ALK-positive controls given any second-line therapy (median overall survival not reached 95% CI 14 months to not reached vs 6 months 4–17, 1-year overall survival 70% 95% CI 50–83 vs 44% 23–64, and 2-year overall survival 55% 33–72 vs 12% 2–30; hazard ratio 0·36, 95% CI 0·17–0·75; p=0·004). Survival in 56 crizotinib-treated, ALK-positive patients was similar to that in 63 ALK-negative, EGFR-positive patients given EGFR TKI therapy (median overall survival not reached 95% CI 17 months to not reached vs 24 months 15–34, 1-year overall survival 71% 95% CI 58–81 vs 74% 61–83, and 2-year overall survival 57% 40–71 vs 52% 38–65; p=0·786), whereas survival in 36 crizotinib-naive, ALK-positive controls was similar to that in 253 wild-type controls (median overall survival 20 months 95% CI 13–26 vs 15 months 13–17; p=0·244). Interpretation In patients with advanced, ALK-positive NSCLC, crizotinib therapy is associated with improved survival compared with that of crizotinib-naive controls. ALK rearrangement is not a favourable prognostic factor in advanced NSCLC. Funding Pfizer Inc, V Foundation for Cancer Research.
Vertebral compression fractures (VCFs) are increasingly observed after spine stereotactic body radiation therapy (SBRT). The aim of this study was to determine the risk of VCF after spine SBRT and ...identify clinical and dosimetric factors predictive for VCF. The analysis incorporated the recently described Spinal Instability Neoplastic Score (SINS) criteria.
The primary endpoint of this study was the development of a de novo VCF (ie, new endplate fracture or collapse deformity) or fracture progression based on an existing fracture at the site of treatment after SBRT. We retrospectively scored 167 spinal segments in 90 patients treated with spine SBRT according to each of the 6 SINS criteria. We also evaluated the presence of paraspinal extension, prior radiation, various dosimetric parameters including dose per fraction (≥20 Gy vs <20 Gy), age, and histology.
The median follow-up was 7.4 months. We identified 19 fractures (11%): 12 de novo fractures (63%) and 7 cases of fracture progression (37%). The mean time to fracture after SBRT was 3.3 months (range, 0.5-21.6 months). The 1-year fracture-free probability was 87.3%. Multivariate analysis confirmed that alignment (P=.0003), lytic lesions (P=.007), lung (P=.03) and hepatocellular (P<.0001) primary histologies, and dose per fraction of 20 Gy or greater (P=.004) were significant predictors of VCF.
The presence of kyphotic/scoliotic deformity and the presence of lytic tumor were the only predictive factors of VCF based on the original 6 SINS criteria. We also report that patients with lung and hepatocellular tumors and treatment with SBRT of 20 Gy or greater in a single fraction are at a higher risk of VCF.
Abstract Introduction Molecular testing to identify targetable driver mutations is the standard of care for patients with advanced stage non-small cell lung cancer. Recent guideline recommendations ...by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) established a benchmark turnaround time (TAT) target of 10 working days for results to be available to the treating oncologist and 3 days or less for specimens to arrive at a commercial testing laboratory if testing is not performed in-house. Methods and Materials To provide insights as to the pre-testing, post-testing, and testing intervals that comprise the overall TAT target, a detailed workflow analysis of 157 lung cancer specimens sent out for molecular testing at a commercial vendor from a single academic medical center during the calendar year 2015 was performed. Results Overall, 128 (81.5%) specimens met the recommended 10 working day TAT, with a median total TAT of 9 weekdays (mean±SD = 9.17±4.15 days). The pre-testing interval was three days or less for 146 (93.0%) specimens, and the post-testing reporting interval was less than one day for 116 (73.9%) cases. TAT variance was not related to intrinsic specimen characteristics. Conclusions In total, the findings indicate that the CAP/IASLC/AMP TAT guideline recommendations are feasible in the majority of lung cancer specimens when a streamlined system is in place.
The development of immune-related adverse events (irAEs) has been associated with improved efficacy of immune checkpoint inhibitors in patients with urothelial cancer, melanoma, and NSCLC. Whether ...this association exists in patients with SCLC is currently unknown.
We conducted a multicenter retrospective study to evaluate the relationship between irAEs and immunotherapy efficacy in SCLC. To account for the lead-time bias resulting from the time-dependent nature of irAEs, the development of irAEs was considered as a time-varying covariate in univariate and multivariate Cox proportional hazard models.
Of the 183 patients treated with immunotherapy, 73 (39.9%) experienced at least one irAE. A total of 42 patients (22.9%) had grade 1 to 2 irAEs, whereas 31 patients (16.9%) had grade 3 to 4 irAEs. The median time of onset to the first irAE was 24 days (interquartile range: 14–55). The baseline clinicopathologic features were well-balanced between patients with and without irAEs. At a median follow-up of 24 months (95% confidence interval CI: 17.0–31.6), the median progression-free survival was significantly longer in the irAE group than the non-irAE group (3.8 versus 1.3 mo, p < 0.0001). The median overall survival was also significantly longer among patients with irAEs than patients without irAEs (13.8 versus 2.9 mo, p < 0.0001). When analyzed as a time-varying covariate, the development of irAEs was associated with a significant improvement in progression-free survival (hazard ratio: 0.44 95% CI: 0.29–0.66, p < 0.001) and overall survival (hazard ratio: 0.47 95% CI: 0.32–0.71, p < 0.001) in multivariate models.
The development of irAEs is associated with improved clinical outcomes for immunotherapy in patients with advanced SCLC.
The EGFR-A763_Y764insFQEA is a unique exon 20 insertion mutation (∼5% to 6% of exon 20 insertions), which, at the structural and enzyme kinetic level, more closely resembles EGFR tyrosine kinase ...inhibitor (TKI)–sensitizing mutants, such as EGFR exon 19 indels and L858R. A limited number of preclinical models and clinical reports have studied the response of this mutant to EGFR TKIs.
We used models of EGFR-A763_Y764insFQEA and more typical EGFR exon 20 insertion mutations to probe representative first- (gefitinib, erlotinib), second- (afatinib), third-generation (osimertinib), and in-development EGFR exon 20–specific (poziotinib, mobocertinib TAK-788) TKIs. We also compiled outcomes of EGFR-A763_Y764insFQEA-mutated lung cancers treated with EGFR TKIs.
Cells driven by EGFR-A763_Y764insFQEA were consistently sensitive to EGFR TKIs (as opposed to those driven by typical EGFR exon 20 insertions A767_V769dupASV, D770_N771insSVD and H773_V774insH), which were only inhibited by in-development EGFR TKIs at doses below those affecting wild-type EGFR. Most case instances (62.5% 95% confidence interval: 39%–86%, n = 16) with lung cancers harboring EGFR-A763_Y764insFQEA responded to clinically available EGFR TKIs (including osimertinib) and to in-development EGFR exon 20-specific TKIs (including mobocertinib) with prolonged periods of progression-free survival in some cases. Median overall survival for EGFR TKI–treated cases was 22 months (95% confidence interval: 16–25). Mechanisms of acquired TKI resistance of this mutant remain underreported, but do seem to align with those of common mutations.
To our knowledge, this is the largest report to confirm that the EGFR-A763_Y764insFQEA mutation is sensitive to clinically available first-, second-, third-generation, and in-development EGFR TKIs.
The risk of rectal toxicity during and after prostate cancer radiation therapy is common to all treatment regimens. Hydrogel rectal spacers are increasingly being used to mitigate this risk and to ...facilitate dose-escalation, but also may infiltrate the rectal wall, with unclear clinical implication. We present a case of significant infiltration associated with severe late rectal injury (grade 4) and further grade 3 to 4 sequelae (recto-urethral fistula and associated osteomyelitis requiring exenteration) after high-dose stereotactic body radiation therapy for localized prostate cancer. The injury's temporal pattern associated with the expected timing of gel dissolution and displacement of infiltrated rectal layers potentially toward high dose regions together suggest a contributing role of the infiltration to the injury. In light of the rapid increase of hydrogel rectal spacer utilization, we review the case's evolution, concerning imaging findings, and associated literature and make suggestions regarding treatment planning and endoscopic assessment in the setting of infiltration or expected injury.
EGFR exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR tyrosine kinase inhibitors (EGFR TKIs). Novel EGFR TKIs have been developed or ...repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).
We used models of EGFR mutations to probe representative first, second, third generation, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.
Cells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH, and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit the phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to greater than 200-fold resistance in proliferation assays probing mobocertinib and osimertinib. A review of clinical studies of mobocertinib disclosed responses that could be lasting.
This is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; and EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.
ALK internal deletions of nonkinase domain exons occur in 0.01% of lung cancers with ALK genomic aberrations. We report a lung adenocarcinoma with a previously undescribed somatic ALK deletion of ...exons 2 to 19 with dramatic and sustained (>23 mo) response to alectinib. Our and other reported cases with ALK nonkinase domain deletions (between introns and exons 1–19) can display positive results in nonsequencing-based lung cancer diagnostic tests (such as immunohistochemistry) used to screen for more common ALK rearrangements. This case report emphasizes that “ALK-driven” lung cancers should be expanded to encompass those harboring not only ALK rearrangements with other genes but also ALK nonkinase domain deletions.
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