World Conference on Lung Cancer 2013 Highlights

BEYOND: Bevacizumab and Chemotherapy in the Chinese Population¹

The vascular endothelial growth factor (VEGF) inhibitor bevacizumab has been shown previously to be effective at extending overall survival (OS)²and progression-free survival (PFS)^2,3when combined with platinum-doublet chemotherapy in the first-line setting to treat advanced nonsquamous non-small cell lung cancer (NSCLC). Since the pivotal studies of bevacizumab included mainly Caucasian patients, the BEYOND trial, which was conducted and presented by Caicun Zhou, MD, and colleagues, aimed to confirm its efficacy in the Chinese population.

Patients aged 18 years or older with histologically or cytologically confirmed, locally advanced, metastatic or recurrent advanced nonsquamous NSCLC with no prior treatment who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomized in a 1:1 ratio to receive CP (intravenous paclitaxel 175 mg/m²and intravenous carboplatin [AUC 6 mg/mL×min] on day 1 of each 3-week cycle for up to 6 cycles), plus either placebo or bevacizumab 15 mg/kg on day 1 of each cycle. Treatment was continued until progression, unacceptable toxicity, withdrawal of patient consent, or death. The primary endpoint was PFS in the intent-to-treat (ITT) population. Secondary endpoints included objective response rate (ORR), OS, exploratory biomarkers, and safety.

A total of 276 patients were randomized into the study, with 138 patients enrolled in each treatment arm. The baseline characteristics were similar in both treatment groups. In the ITT population, patients in the CP-plus-bevacizumab group had a prolonged PFS compared with patients in the CP-plus-placebo group (hazard ratio [HR] = 0.40; 95% CI, 0.29-0.54), with a median PFS of 9.2 months versus 6.5 months, respectively (P<.0001). The ORR was also improved when bevacizumab was added to CP (54.4% vs 26.3% with CP + placebo). The disease control rates (DCRs) were 94.4% with CP plus bevacizumab compared with 88.7% with CP plus placebo. The median duration of response was 8.0 months with CP plus bevacizumab compared with 5.3 months with CP plus placebo. At the time of the conference, OS data were not yet mature.

Safety data from BEYOND were similar to those seen in previous studies of CP plus bevacizumab in NSCLC. No new safety signals were observed. Treatment-related deaths were low in both arms (2.2% CP + bevacizumab vs 0 CP + placebo). Adverse events were the cause of treatment discontinuation in 18.4% of patients in the CP-plus-bevacizumab arm compared with 15.0% of patients in the CP-plus-placebo arm.

RTOG 0617: Standard or High-Dose Radiation With or Without Cetuximab⁴

The BEYOND study confirmed that adding bevacizumab to first-line platinum-based chemotherapy appears to provide similar PFS benefits to Chinese patients with advanced nonsquamous NSCLC as it does with global populations, with no new safety concerns to report.The results of the Radiation Therapy Oncology Group (RTOG) 0617 trial comparing OS differences between standard-dose (60 Gy) and high-dose (74 Gy) radiotherapy with concurrent chemotherapy and comparing standard chemoradiotherapy with the addition of cetuximab in an unselected population were presented. Cetuximab, a monoclonal antibody toEGFR, is used in combination with chemotherapy in metastatic NSCLC and head and neck cancer, and with radiotherapy in locally advanced head and neck cancer.

&ldquo;As background, when the RTOG 0617 trial was designed nearly 10 years ago, the standard of care for unresectable, stage III NSCLC was a combination of chemotherapy and radiation, employing a radiation dose of approximately 60 Gy. Retrospective analysis and conventional wisdom suggested that escalating the dose of radiation may help improve outcomes. Phase I and II trials have showed that radiation doses as high as 74 Gy could be delivered safely with chemotherapy, and suggested improvement in both local and regional control, and potentially overall survival,&rdquo; said Gregory A. Masters, MD, medical oncologist at the Helen F. Graham Cancer Center in Newark, Delaware. In addition, he said, &ldquo;Cetuximab had shown efficacy in combination with chemotherapy in stage 4 disease, and the phase II study RTOG 0324 suggested promising results when cetuximab was added to chemoradiation in stage 3 NSCLC, with a 49% 2-year survival and a median survival of 22.7 months.&rdquo;

This phase III intergroup trial randomized patients using a 2&times;2 factorial design. Concurrent chemoradiotherapy (CRT) included weekly paclitaxel (45 mg/m²) and carboplatin (AUC 2 mg/mL&times;min). Patients randomized to cetuximab received a 400-mg/m²loading dose on day 1 followed by weekly doses of 250 mg/m². All patients were to receive two cycles of consolidation chemotherapy. The data presented at WCLC included the initial survival outcome in the cetuximab analysis.

Of the 544 patients enrolled, 419 were eligible for the radiotherapy and 465 for the cetuximab analyses, with a median follow-up of 18.7 months. Median survival was 23.1 versus 23.5 months, and 18-month OS was 60.8% and 60.2% for cetuximab compared with no cetuximab, respectively (P=.484; HR = 0.99), which crossed a protocol-specified futility boundary for early reporting. Median survival was 28.7 months versus 19.5 months, and 18-month OS was 66.9% versus 53.9% for standard-dose and high-dose radiotherapy, respectively (P=.0007; HR = 1.56). &ldquo;There was no difference in overall survival based on cetuximab,&rdquo; confirmed Masters. In addition, there was no significant interaction between the radiotherapy dose and the use of cetuximab.

Grade &ge;3 nonhematologic toxicities were more common in the cetuximab group than the no-cetuximab group (70.5% vs 50.7%;P<.0001). In these treatment arms, grade 4 or 5 events were reported by 35.8% and 28.2% of patients, respectively.

CTONG 0806: Pemetrexed vs Gefitinib for Wild-Type EGFR⁵

Masters concluded that, &ldquo;Cetuximab did not improve overall survival or progression-free survival in this population of stage 3 NSCLC patients when added to chemoradiotherapy. Cetuximab did, however, significantly increase grade 3 to 5 toxicities when compared to chemoradiation alone. As presented by Dr. Jeff Bradley at this year&rsquo;s ASCO meeting, high-dose radiation isnotsuperior to standard-dose radiation in this group of patients with unresectable, stage III NSCLC. Patients receiving higher doses of radiation had an increased risk of death, an increased risk of local failure, and increased toxicity when compared to standard-dose radiation with chemotherapy.&rdquo;&ldquo;In the past, our drug treatments were the same for everyone, and they had considerable toxicities, so, in terms of helping people live longer, there was some offset in terms of people not living better. It&rsquo;s well established now that if you can select patients for specific treatments, their outcomes might be improved,&rdquo; said Paul A. Bunn, Jr, MD, the James Dudley Chair in Cancer Research at the University of Colorado School of Medicine, and the executive director of the IASLC for 10 years.

Both pemetrexed, a standard cytotoxic drug, and gefitinib, a drug targeted toEGFRmutations, are standard second-line treatments for advanced nonsquamous NSCLC in East Asia, but it is not known which drug performs better as second-line therapy in patients who do not have activation in theEGFRtarget, which is the case for the majority of patients. The CTONG 0806 study was performed by the Chinese Thoracic Oncology Group to compare the efficacy of pemetrexed with that of gefitinib in the second-line setting for patients with advanced nonsquamous NSCLC with wild-typeEGFR. CTONG 0806 was a phase II, multicenter, randomized, controlled, open-label trial with the primary endpoint of PFS whose results were presented by Qing Zhou, MD, and colleagues from Guangdong Lung Cancer Institute in China.

A total of 157 evaluable patients with locally advanced or metastatic nonsquamous NSCLC who were previously treated with platinum-based chemotherapy, and who had wild-typeEGFRas detected by direct sequencing, were randomized to receive oral gefitinib 250 mg/day (n = 81) or intravenous pemetrexed 500 mg/m²(n = 76) on day 1 every 21 days until disease progression or unacceptable toxicity. Secondary endpoints included 4-month and 6-month PFS rates, OS, ORR, DCR, quality of life, and safety.

Baseline characteristics were similar between treatment arms. Median PFS was significantly longer for pemetrexed (4.8 months) compared with gefitinib (1.6 months; HR = 0.54; 95% CI, 0.40-0.75;P<.001), which was confirmed by Independent Review Committee (5.6 vs 1.7 months; HR = 0.53; 95% CI, 0.38-0.75;P<.001). Significant differences in outcomes between the two arms were also seen for 4-month PFS, 6-month PFS, and DCR. In addition, median OS was numerically higher in the pemetrexed arm (12.4 months vs 9.6 months with gefitinib; HR = 0.72; 95% CI, 0.49-1.04;P=.077).

More skin rash and diarrhea were reported in the gefitinib arm, whereas more fatigue and more increases in alanine amino transferase (ALT) were seen with pemetrexed. Grade 3 or 4 adverse events occurred in significantly more patients treated with pemetrexed than gefitinib (32.9% vs 12.3%, respectively;P=.002).

In 108 patients with sufficient tumor tissue,EGFRmutation status was tested again with the more sensitive Scorpion amplification refractory mutation system (ARMS), which revealed that 32 patients were actuallyEGFR-positive. In the 76 patients who were confirmed to have wild-typeEGFRby ARMS (35 in pemetrexed arm and 41 in gefitinib arm), the median PFS changed to 4.0 months with pemetrexed compared with 1.3 months with gefitinib (HR = 0.42; 95% CI, 0.26-0.67;P<.001), and the ORRs changed from about 13% in both treatment arms to 11.4% in the pemetrexed arm and 2.4% in the gefitinib arm for the patients whose wild-typeEGFRstatus was confirmed with ARMS. These patients are said to have &ldquo;low abundances&rdquo; ofEGFRmutations.⁶Therefore, &ldquo;The patients who were truly without an EGFR mutation did not benefit from gefitinib,&rdquo; explained Bunn.

PD-1 Immunotherapy With MK-3475⁷

&ldquo;This study will likely change the way patients with advanced nonsquamous NSCLC are treated with second-line therapy,&rdquo; said Zhou, as &ldquo;it is the first trial to show significant improvement in PFS, DCR, and a trend of improved OS in the pemetrexed arm compared with gefitinib in the second-line setting forEGFRwild-type advanced nonsquamous NSCLC. In the second-line setting, we can see thatEGFRstatus should be determined to guide treatment choice, and ARMS is better than direct sequencing in defining the exact population who may benefit from EGFR TKI treatment. In the second-line setting for theEGFRwild-type population with nonsquamous NSCLC, pemetrexed should be recommended.&rdquo;The objective responses achieved with currently approved cytotoxic chemotherapies for previously treated patients with NSCLC are few and of short duration, and have limited impact on PFS and OS. Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that activates with its ligands, PD-L1 or PD-L2, leading to the suppression of antitumor immunity. Preclinical and clinical data have indicated that the PD-1 pathway is important in NSCLC. Edward Garon, MD, David Geffen School of Medicine at UCLA, Los Angeles, California, and colleagues elsewhere reported preliminary clinical safety and efficacy data of MK-3475, a humanized monoclonal immunoglobulin G4 (IgG4) antibody against PD-1.

In order to participate in the trial, patients were required to have NSCLC that was previously treated with two systemic regimens, at least one measurable tumor lesion, an ECOG performance status of 0 or 1, adequate laboratory function, and a new tumor biopsy no more than 60 days before the first study dose. Eligible patients were enrolled to receive MK-3475 administered at 10 mg/kg every 3 weeks. Imaging assessments were performed by the investigators every 9 weeks until confirmed disease progression utilizing the immune-related response criteria (irRC). Independent central review of imaging results used RECIST v1.1. PD-L1 expression on the pretreatment tumor sample was determined by immunohistochemistry. A cut-point associated with the Youden Index of the receiver-operating characteristic curve for PD-L1 staining was identified.

A total of 38 patients were enrolled between April and September 2012. Their median age was 63 years (range, 34-85 years), with 42% men and 42% with an ECOG performance status of 0. Previously treated, stable brain metastases were permitted on study; these were present in 10% of patients. Molecular analysis revealed seven patients with anEGFRmutation, eight patients with aKRASmutation, and one patient with aALKrearrangement.

Half of the patients experienced drug-related adverse events (AEs). The most common were fatigue, rash, and pruritus (16% each), with diarrhea reported by 13% of patients (all grade 1 or 2). One drug-related grade 3-4 AE (grade 3 pulmonary edema, 3%) was reported. There were no drug-related fatalities.

Using the irRC, investigators determined that the ORR (confirmed and unconfirmed) was 24%, including both squamous and nonsquamous subtypes. The results obtained by independent central review using RECIST v1.1 criteria were similar, yielding an ORR (confirmed and unconfirmed) of 21%. Most of the responses assessed by irRC criteria were observed by the time of the first planned assessment, which occurred at week 9. The median duration of response by irRC has not yet been reached, with a median duration of follow-up to date of 9 months (minimum, 6 months). As of June 2013, seven of the nine patients who responded as per irRC continue on study medication.

Pretreatment PD-L1 expression in the tumor was found to be a statistically significant predictor of response. Among the patients with evaluable tumor PD-L1 expression, all of the confirmed responses via both RECIST v1.1 and irRC criteria occurred in patients who had tumors that were strongly positive for PD-L1.

Alectinib, a Second-Generation ALK Inhibitor⁸

The investigators concluded that MK-3475 was found to be generally well tolerated in patients with advanced, previously treated NSCLC, and that it provided durable objective responses. Enrollment is ongoing for an additional cohort of patients whose tumors express PD-L1.Anaplastic lymphoma kinase (ALK) is a tyrosine kinase constitutively activated following chromosomal translocation in 3% to 7% of all NSCLC cases. Patients withALKtranslocation usually respond to the ALK inhibitor crizotinib with a median duration of response of approximately 10 months. &ldquo;It is estimated that there over 60,000 cases ofALK-positive NSCLC each year worldwide, and there is a critical need for effective treatments in these patients,&rdquo; said Shirish Gadgeel, MD, of the Karmanos Cancer Institute in Detroit, Michigan. Despite a response rate of 60% with crizotinib, patients do eventually progress, and one important area of progression is brain metastases, according to Gadgeel. Alectinib (CH5424802) is a second-generation ALK inhibitor that is more potent and specific than crizotinib, and it is being studied as a potential treatment for patients with NSCLC who haveALKgene rearrangement. Gadgeel and colleagues presented results of a phase I dose-escalation study of alectinib in patients with NSCLC who had failed crizotinib therapy.

Patients were eligible to participate if they had prior progression on crizotinib, an ECOG performance status of 0 to 2, adequate organ functions, andALKrearrangement that was confirmed by an FDA-approved test. Symptomatic central nervous system (CNS) metastases were allowed, but were required to be treated before study participation. Alectinib was administered orally at twice-daily doses of 300 mg, 460 mg, 600 mg, 760 mg, and 900 mg until a lack of clinical benefit was perceived. Pharmacokinetic sampling was performed, and efficacy was assessed by the RECIST v1.1.

A total of 47 patients were enrolled. No dose-limiting toxicities were observed. Only one patient required dose modification due to grade 2 fatigue. Some of the most common AEs were fatigue (30%), myalgia (17%), and peripheral edema (17%). According to Gadgeel, most of these events were grade 1, and were reported in patients being treated with the higher doses of twice-daily alectinib 750 mg and 900 mg. Grade 3 and 4 toxicities were fairly uncommon; the only ones judged to be treatment-related were increase in &gamma;-glutamyl transpeptidase, decrease in neutrophils, and hypophosphatemia (each, n = 2). No grade 3 nausea, vomiting, diarrhea, or edema were reported.

The ORR was about 54.5%, but at dosages of 460 mg twice daily and higher, the ORR was 59.5%. Twenty-four of the 47 patients received the drug for 120 days or more. The 600-mg twice-daily dosage was selected as the recommended phase II dosage of alectinib based on safety, efficacy, and pharmacokinetic results.

Due to crizotinib&rsquo;s inability to cross the blood-brain barrier, Gadgeel explained that an important site of progression in crizotinib-treated patients is brain metastases, as well as leptomeningeal metastases. In this study, responses in brain metastases were observed after alectinib treatment, including near complete clearance of leptomeningeal metastases in one patient after 6 weeks.

Gadgeel concluded that, &ldquo;Alectinib is a highly selective ALK inhibitor with significant activity in ALK+ NSCLC patients previously treated with crizotinib that has shown activity in CNS metastases and appears to be well tolerated. The drug has recently received Breakthrough Therapy designation by the FDA.&rdquo;

References

Based on these findings, a global phase II study to evaluate alectinib in crizotinib-refractory patients is currently being performed (NCT01801111). &emsp;

1. Zhou C, Chen G, Liu X, et al. BEYOND: a randomized, double-blind, placebo-controlled, multicentre, phase III study of first-line carboplatin/paclitaxel (CP) plus bevacizumab (Bv) or placebo (Pl) in Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer. Presented at: 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract MO06.13.
2. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550.
3. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil.J Clin Oncol. 2009;27(8):1227-1234.
4. Bradley J, Masters GA, Hu C, et al. An intergroup randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) chemoradiotherapy +/- cetuximab (cetux) for stage III non-small cell lung cancer (NSCLC): results on cetux from RTOG 0617. Plenary session. Presented at: 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract PL03.05.
5. Zhou Q, Cheng Y, Zhao M-f, et al; Chinese Thoracic Oncology Group (CTONG). Final results of CTONG 0806: a phase II trial comparing pemetrexed with gefitinib as second-line treatment of advanced non-squamous NSCLC patients with wild-type EGFR. Presented at: 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract O15.07.
6. Zhou Q, Zhang XC, Chen ZH, et al. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer.J Clin Oncol. 2011;29(24):3316-3321.
7. Garon EB, Balmanoukian A, Hamid O, et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC). Presented at: 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract MO18.02.
8. Gadgeel S, Ou S-H, Chiappori AA, et al. A phase 1 dose escalation study of a new ALK inhibitor, CH5424802/RO5424802, in ALK+ non-small cell lung cancer (NSCLC) patients who have failed crizotinib (AF-002JG/NP28761, NCT01588028). Presented at: 15th World Conference on Lung Cancer; October 27-30, 2013; Sydney, Australia. Abstract O16.06.