Lung Cancer Highlights from ASCO 2012

Marina C. Garassino
Eva R. Haspinger

Treating metastatic lung cancer is becoming increasingly challenging and we selected four abstracts, that may have a certain impact in the clinical practice.
In our opinion anti-PD-1 wins  the prize of “the most promising drug of 2012 in NSCLC”. BMS – 936558 is a fully human mAb that blocks the programmed death-1 (PD-1) co-inhibitory receptor expressed by activated T-cells. BMS-936558 was administered IV Q2WK to 240 pts with various solid tumours, including 75 pts with NSCLC, at doses of 0.1 to 10 mg/kg during dose-escalation and/or cohort expansion. Patients with advanced NSCLC previously treated with at least one prior chemotherapy regimen were eligible. Common related AEs were fatigue (17%), nausea (11%), pyrexia (7%), pruritus (7%), dizziness (7%), and anaemia (7%). The incidence of grade 3-4 related AEs was 8%. Clinical activity was observed at all dose levels and in multiple histologies. Several patients achieved prolonged SD. At the time of data lock, of 10 OR pts, 3 had responses lasting ≥6 mo and 5 were on study with response duration of 1.8-5.5 months.  

Our comments is that the drug is active and promising, however it is still to debate whether the use of RECIST 1.1 and the time of re-evaluation with drugs targeting the immune system are appropriate to really assess the activity of the drug and in particular of all these strategies.

LUX LUNG 3

A randomised phase III study comparing afatinib over cisplatin pemetrexed combination as first-line treatment for patients with advanced adenocarcinoma of the lung harbouring every EGFR-activating mutations. The primary end point was progression free survival. Following central testing for EGFR mutations 1269 patients were screened, 345 pts (stage IIIB/IV, PS 0–1, chemo-naive) were randomized 2:1 (A: 230; PC: 115) to receive either daily A 40 mg or iv PC (500 mg/m2 + 75 mg/m2 q21 days up to 6 cycles). The study included also patients with rare mutations and not only common mutations as Del19/L858R. The preclinical hypothesis was that irreversible tyrosine kinase inhibitors could overcome resistance mutations of EGFR as T790M. The study met his primary endpoint and demonstrated that treatment with afatinib significantly prolonged PFS compared to PC with a HR 0.58 (0.43 – 0.78). The subgroup analysis can assume that patients with mutations of exon 19 particularly benefit from this treatment.
Our criticisms are the role of afatinib in patients with rare mutations and in particular with mutations conferring resistance to EGFR inhibitors, such as the majority of exon 20 mutations. Toxicity are as expected, however a significant percentage of nail toxicity and diarrhoea were observed. LUX LUNG 3 is an important study that moves up front afatinib in patients harbouring EGFR mutations. It remains to understand the role of afatinib compared to gefitinib that will be further assessed by the LUX LUNG 7 trial, while the role compared with erlotinib will be unexplored.

TAILOR

A phase III multi centre Italian trial comparing erlotinib with docetaxel as second-line treatment of NSCLC patients with wild-type (wt) EGFR. This is an independent trial supported by the italian regulatory drug agency AIFA (Agenzia Italiana del Farmaco). The primary end point was overall survival, secondary end points were progression free survival (PFS) and response rate (RR). Erlotinib, based on the BR21 study, has been studied as second and third line treatment only in patients unfit for every chemotherapy, regardless of their mutational status. Five studies compared EGFR TKIs over chemotherapy, however molecular analyses were performed only in less than 18% of patients with post hoc and unplanned analyses, therefore the role of erlotinib in wild-type patients is still controversial. EGFR and KRAS mutational status were cross validated by direct sequencing and confirmed by RFLP at the same time in two independent labs in all eligible patients; only patients with wt EGFR (exons 19, 21) at progression, and previously treated with a first line platinum-based taxan free regimen, were randomized to receive either erlotinib (112 pts) daily or docetaxel (110 pts) 3-weekly or weekly. In 2011 based on astrong suggestion of the IDMC the study was emended, however the primary endpoint remained overall survival and the study design never changed but lost only its power to determine whether KRAS, EGFR status (FISH) and EGFR expression (IHC) were predictive factors. The study met the secondary endpoint with a HR 0.69 (95%CI 0.52-0.93 p=0.014) in favour of chemotherapy. The benefit of chemotherapy was maintained in all the subgroup analyses considered. In particular, KRAS has not been demonstrated to have either prognostic or predictive value in this subset of patients. Toxicity in the docetaxel arm seemed underestimated because two different schedules of docetaxel were used.

For reason of time some data could not be not enough detailed during the oral presentation. Data on PFS which is only the secondary endpoint as clearly stated in the protocol and when all target patients were randomized were presented. There was no imbalance in patients between the two groups according to the best response achieved in first-line, PS, KRAS and the small imbalance for histology and smoking habits did not demonstrate any value in the multivariate analysis. Despite two different regimens in the docetaxel arm (weekly and 3-weekly schedule), the median time to assessment in the two arms was the same (9.3 weeks in the erlotinib arm and 9.2 weeks for docetaxel). The protocol did not include independent radiological review was planned because the primary endpoint never changed and was the OS. However,  the steering committee is evaluating to independently review all CT scans to strengthen the results. All the authors clearly and strongly state that a final balance of the trial will be done only when OS data will be presented.

PARAMOUNT

The trial was already presented at ASCO 2011 and met his primary showing that pemetrexed continuation maintenance therapy significantly reduced the risk of disease progression over placebo (HR=0.62; 95% CI: 0.49-0.79; p <0.0001) in patients with advanced NS NSCLC who had not progressed during pemetrexed –cisplatin induction. Disease control rate was 71.8% in the pemetrexed arm and 59.6% in the PL arm (p=0.009). This year data on overall survival (OS) were presented. 539 pts who had not progressed during induction (4 cycles of pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 were randomized (2:1) to maintenance pemetrexed (500 mg/m2, on day 1 of 21-day cycles) plus BSC or placebo plus BSC until disease progression. Pemetrexed resulted in a statistically significant 22% reduction in risk of death with a HR=0.78 (95% CI 0.64 – 0.96) p=0.0195 corresponding to an advantage in terms of months from 11.0 to 13.9 months. The HR was the same when measured from the beginning of induction, in terms of months 14.0 vs 16.9.
Our comments are that the study is very well conducted, the maintenance seems feasible and well tolerated. The only criticism is that although there are no data supporting the evidence that patients achieving a response in the induction treatment must have six platinum pemetrexed cycles, it is common clinical practice “go to six”. Furthermore, it remains to be still clarified which patients benefit of continuous maintenance or switch maintenance.

References

  1. Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer N Eng J Med 6, 2012 1-12
  2. LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. J Clin Oncol 30, 2012 (suppl; abstr LBA7500)
  3. TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type (wt) EGFR. J Clin Oncol 30, 2012 (suppl; abstr LBA7501)
  4. PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). J Clin Oncol 30, 2012 (suppl; abstr LBA7507

Marina Garassino Eli Lilly, Boheringer Ingelheim

Lung Cancer Highlights from ASCO 2012
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