Two phase I clinical trials that have investigated the safety and efficacy of the erlotinib-pemetrexed combination have been reported. In the first study by Ranson et al. [17
], where both agents were started on the same day, DLTs were not experienced at doses of up to 150
mg/day of erlotinib plus 600
of pemetrexed; the RD was determined as being equal to each of the licensed single-agent doses (150
mg daily and 500
days, respectively). In the second study by Davies et al. [18
], the RD and administration schedule was fixed at a dose of 250
mg from day 2 to 16 for erlotinib and 500
on day 1 for pemetrexed every 21
days. We used the same RD as in the first trial with an identical administration schedule to that used in the second trial, and have now moved to an ongoing phase II trial.
As for the safety profile, observed AEs were consistent with those reported in the former two phase I studies [17
]. The most frequent AE was skin/dermal disorder, which was compatible with that reported in the previous studies of erlotinib monotherapy [19
]. Other major AEs were hematologic disorders, ALT elevation and gastrointestinal disorders, which were commonly observed in monotherapy involving either agent. However, the majority of them were grade 1/2 and controllable. Additive toxicities of erlotinib and pemetrexed administered in combination seemed to be marginal compared with those observed in previous studies of either agent alone [11
]. No patient experienced interstitial lung disease. Consequently, administrating intermittent erlotinib with pemetrexed was shown to be safe and tolerable.
The latest randomized phase II study involving pretreated nonsquamous NSCLC patients demonstrated that, as compared with pemetrexed (500
, day 1) alone, combination of pemetrexed (500
, day 1) with daily erlotinib (150
mg) significantly improved both median progression-free survival (3.2
<0.01) and overall survival (11.8
0.019), although the RR (17.1% vs
. 10.8%) and DCR (55.8% vs
. 51.8%) did not differ between the single and combined treatments [21
]. Even though the design of this study differed from ours in that the erlotinib administration schedule was daily rather than intermittent, and that collection of EGFR
mutation status data was discretionary rather than mandatory, the significant survival benefit brought about by this combination therapy has encouraged us to continue our ongoing phase II study until we have overall survival data.
When evaluated on the basis of RECIST two EGFR
-mutated patients did not respond in our study. However, one patient with a L858R mutation in exon 21 practically achieved a PR. The other with a G719S mutation in exon 18 succeeded in maintaining a long SD, which was also practically beneficial, considering that in patients with the G719X mutation the reported RR to EGFR-TKIs was approximately 56% [22
]. Collectively, the erlotinib and pemetrexed combination is not only well-tolerated, but also attractive in terms of antitumor efficacy, regardless of EGFR
However, our study had a number of limitations. First, pharmacokinetic analysis of the two agents was not conducted and potential interactions were not investigated. Second, QOL was not assessed by questionnaire. QOL assessment would have been helpful in understanding the impact of AEs, since there was a high rate of them even though most were grade 1 or 2. These issues should be addressed in future trials.
Recently, maintenance therapy following platinum-doublet front-line therapy has been approved, as long as the treatment regimen has tolerable and noncumulative toxicity profiles. Pemetrexed and erlotinib have been shown to be effective and tolerable when used as single-agent maintenance therapy [23
], and were approved as suitable agents for this purpose by the US-Food and Drug Administration in 2009 and the European Medicines Agency in 2010. Since we have now demonstrated the safety and possible efficacy of the combined use of these two agents in the current phase I study, it would be very interesting to compare the therapeutic efficacy of this combination with that of the two agents administered separately in a maintenance setting in the near future; no studies of this design have been reported to date.
In conclusion, the present study indicated that intermittent erlotinib (150
mg on days 2 to 16) in combination with pemetrexed (500
on day 1) when administered every 21
days is a feasible and well-tolerated regimen. A multi-centered, single-arm phase II study is currently ongoing to evaluate the efficacy and safety of this combination regimen.