GILT study: Oral vinorelbine (NVBo) and cisplatin (P) with concomitant radiotherapy (RT) followed by either consolidation (C) with NVBo plus P plus best supportive care (BSC) or BSC alone in stage (st) III non-small cell lung cancer (NSCLC): Final results of a phase (ph) III study

Reporter: Annemarie Fernandes
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 4, 2012

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Presenter: Rudolf M. Huber, MD, PhD, FCCP
Presenter's Affiliation: Medizinische Klinik Innenstadt, München, Germany

Background

  • Concurrent chemo-radiotherapy (CT-RT) is considered the standard treatment for patients with stage III NSCLC.
  • Treatment failure in patients with NSCLC, particularly locally advanced NSCLC, is predominantly distant. These distant failures likely drive the poor rates of overall survival in this disease.
  • As a result, the use of consolidation chemotherapy after definitive chemoradiation has been under investigation to potentially decrease the risk of distant failure and improve overall survival.
  • The RTOG 0139 study (Albain, Lancet, 2009) evaluated induction chemoradiation followed by surgery vs. definitive chemoradiation and used 2 cycles of consolidation chemotherapy with cisplatin/etoposide in both arms with favorable results.
  • The HOG study (Hanna et al., JCO, 2008) randomized patients with locally advanced NSCLC to 3 cycles of consolidation docetaxel vs. observation after definitive treatment with concurrent chemoradiation. There was no difference in overall or progression-free survival with or without consolidation docetaxel and the patients who received docetaxel had a higher incidence of hospitalization, pneumonitis, and treatment-related death
  • Similarly, a SWOG study (Kelley et al., JCO, 2008) randomized stage III NSCLC patients to gefitinib vs. placebo after treatment with definitive chemoradiation followed by consolidation therapy with docetaxel x 3 cycles. Again, no benefit was noted with additional consolidation/maintenance chemotherapy.
  • Despite the negative results in prior studies, studies are investigating the use of consolidation with different chemotherapy agents, given the strong need to improve distant failure and overall survival rates
  • The current study evaluates the use of consolidation chemotherapy with oral vinorelbine (NVBo) and cisplatin (P) after definitive chemoradiation in patients with stage III NSCLC.

Materials and Methods

  • This is a phase III randomized control trial
  • Inclusion criteria: untreated histologically or cytologically confirmed NSCLC, inoperable stage IIIA (N2) or stage IIIB amenable to definitive chemoradiotherapy
  • Treatment: Patients were treated with definitive chemoradiation and then randomized to Arm A (consolidation chemotherapy + best supportive care) vs. Arm B (best supportive care)
    • Definitive chemoradiation:
      • Chemotherapy: NVBo 50 mg/m² D1, D8, D15 + P 20 mg/m² D1-D4 q4w for 2 cycles
      • Radiation Therapy (RT): 66 Gy in 33 daily fractions of 2Gy, starting on day 1
    • If patients had at least stable disease at the end of CT-RT, they were randomized to:
      • Arm A: NVBo 60-80 mg/m² D1D8 + P 80 mg/m² D1 q3w for 2 cycles + best supportive case
      • Arm B: best supportive care
  • The primary endpoint was progression-free survival (PFS).
  • Secondary endpoints were response rate, overall survival (OS), safety profile, and quality of life. Response rates were assessed 3 months after consolidation phase.

Results

  • From July 2005 to May 2009, 288 patients were enrolled and 279 pts received CT/RT
  • 201 patients (72%) had at least stable disease and were randomized
  • Patients in each arm had similar baseline characteristics. The median age was 60.3 years. About 50% were squamous cell carcinoma and 36% were adenocarcinoma. A larger number of patients had stage IIIB disease (82%).
  • Treatment delivery
    • Only 16 patients were unable to receive chemotherapy during their 2nd cycle
    • 11% of patients required a reduction of >5% of the RT dose
  • Efficacy
    • Median PFS was not statistically significant at 6.4 months (Arm A) vs. 5.5 months (Arm B); p = 0.63
    • Median overall survival was not statistically significant at 20.8 months (Arm A) vs. 18.5 months (Arm B); p = 0.87. 2- year and 4- year OS rates were also similar between the 2 arms. The survival curves are overlapping and demonstrate and initial steep curve followed by a plateau at 20% OS.
    • Patients treated with consolidation chemotherapy had an improved disease control rate (DCR) of 84% vs. 66% in the best supportive care group, p = 0.0084, when analyzing the evaluable population. Upon evaluating patients by intent-to-treat analysis, this result was no longer statistically significant (p=0.12)
    • Overall response rate was not statistically significant between the 2 groups.
    • Patients with squamous cell carcinoma histology had a slightly better overall response rate to definitive chemoradiation (66.9% vs. 57.6% in adenocarcinoma) and consolidation chemotherapy (42.9% vs. 33.3% in adenocarcinoma)
  • Toxicity
    • Hematologic- the major toxicity was expected neutropenia. Grade 3/4 neutropenia was higher in the consolidation chemotherapy group: 11.7% vs. 5.7% in the best supportive care group. There were low rates of febrile neutropenia in both groups (1% in the Arm A vs. 0% in Arm B)
    • No pneumonitis was seen in the consolidation arm, but 2% of patients in the best supportive care arm developed pneumonitis.
    • Patients treated with consolidation chemotherapy experienced slightly higher rates of grade 3 nausea (4.7 vs. 2.9%)

Author's Conclusions

  • The authors conclude that definitive chemoradiation with vinorelbine and cisplatin has a high level of efficacy (OR 60.7%; DCR 86.0%) and low toxicity profile.
  • The disease control rate was significantly improved in patients who received consolidation chemotherapy with vinorelbine and cisplatin (p=0.0084).
  • Consolidation chemotherapy with vinorelbine and cisplatin did not increase lung toxicity, as seen in the HOG study with consolidation docetaxel.
  • However, the authors note that there is no survival advantage for consolidation chemotherapy in this unselected group.

Clinical Implications

  • The data presented here, demonstrating no significant benefit in survival with consolidation chemotherapy, are consistent with multiple prior studies evaluating the role of consolidation chemotherapy after definitive therapy with concurrent chemoradiation in locally advanced NSCLC.
  • Although there was an improvement in disease control rate in evaluable patients receiving consolidation chemotherapy, this result was no longer statistically significant on intent-to-treat analysis.
  • The data related to patterns of failure of quality of life were not available for presentation.
  • The accrual goal of this study was 282 patients. However, of the 288 patients enrolled in this study, only 201 were randomized. The small numbers limit the power of the study and the selection effect may have resulted in bias.
  • Given the pronounced tail on the survival curve at 20% survival, it is possible that certain subgroups of patients may benefit from consolidation chemotherapy. Patients with squamous cell histology appeared to have a more favorable response to treatment compared to patients with adenocarcinoma. Further studies need to focus on identifying these subgroups of patients by analyzing biomarkers of other specific patient or tumor characteristics.
  • Taken together, concurrent CRT without consolidation CT remains the standard of care.


News
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Apr 23, 2014 - In patients with advanced non-small cell lung cancer, new drugs and drug combinations can prolong survival, while hormone therapy among menopausal females with lung cancer is associated with increased mortality risk, according to research presented at the annual meeting of the American Society of Clinical Oncology, held from May 29 to June 2 in Orlando, Fla.



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