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Fotolyn (Pralatrexate) Chemotherapy Beats Tarceva on Survival as Second Line Therapy in Smokers
It’s been two and a half years since I described a phase IIB trial of Fotolyn (pralatrexate), a relatively new chemotherapy agent, being compared to Tarceva (erlotinib) in current or ex-smokers with previously treated advanced NSCLC. The new drug, Fotolyn, is described in a prior post, and it has since been approved by the FDA as a treatment for peripheral T-cell lymphomas, so it’s commercially available in the US. Today, Allos Therapeutics, the company that makes Fotolyn, sent out a press release that the clinical trial is positive for a modest survival advantage vs. Tarceva in this trial of current and former smokers.
A total of 201 patients were enrolled, with a 13% improvement in OS in the overall population (166 included for analysis). In addition, there were some predefined patient groups for subset analysis, which demonstrated that light smokers (I don’t have the precise definitions for light vs. heavy smoking history) did particularly better with Fotolyn (HR 0.63, corresponding to a 37% improvement), as did patients with non-squamous cancers (HR 0.65, corresponding to a 35% improvement). They saw trends in favor of Fotolyn for overall survival in all groups except those with squamous NSCLC and those who received prior Alimta (pemetrexed).
The other side of the coin is drug safety, which showed that mucositis (mouth sores) were moderate to severe in 23% of patients, and other common but typically relatively mild side effects included decreased blood counts (expected with just about all standard chemo agents), fatigue, and shortness of breath (which may have been more from the underlying cancer).
These results are certainly interesting and fairly promising. We would expect that Tarceva’s benefit is not very strong in current smokers or those with a significant smoking history, but Fotolyn didn’t beat Tarceva in heavy smokers, nor was it convincingly better in patients with squamous NSCLC, a group that we think of as receiving pretty minimal to modest benefit with Tarceva. It’s also not clear whether there is anything to the subset analysis that showed no benefit of Fotolyn over Tarceva in patients who received prior Alimta. This wasn’t a large trial, and subset analyses, especially in small trials, can sometimes randomly show differences that aren’t really real, or miss differences that actually exist, because small sample groups are unreliable.
I presume that Allos will pursue in moving Fotolyn forward in NSCLC, in terms of getting FDA approval; this randomized phase IIB trial, very much designed like an underpowered phase III trial, is ostensibly enough to move forward with a larger trial that can lead to FDA approval. The lack of mention of P values in the press release leads me to presume that differences are not significant, but I’m sure we’ll learn more once the results of this trial are presented in an upcoming meeting.
In the meantime, it’s possible that this will lead to some use of Fotolyn in NSCLC patients, at least those with a smoking history, but I expect that getting it covered by insurance may be challenging until we have more data. At the very least, this is a promising lead as a new option to hope to see for current or previously smoking patients with previously treated advanced NSCLC.
6 Responses to Fotolyn (Pralatrexate) Chemotherapy Beats Tarceva on Survival as Second Line Therapy in Smokers
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Thank you, Dr. West, for discussing this. I read the press release this morning, and was unsurprised by the first exception, but puzzled by the second:
“They saw trends in favor of Fotolyn for overall survival in all groups except those with squamous NSCLC and those who received prior Alimta (pemetrexed).”
My first thought was ‘What is there about Alimta that would have such an effect?’. Your point is helpful:
“It’s also not clear whether there is anything to the subset analysis that showed no benefit of Fotolyn over Tarceva in patients who received prior Alimta. This wasn’t a large trial, and subset analyses, especially in small trials, can sometimes randomly show differences that aren’t really real, or miss differences that actually exist, because small sample groups are unreliable.”
Is it also possible that there is some confounding associated with patients who previously received Alimta? (E.g., patients given Alimta were more likely to have x in their history of disease and/or treatment, so they were more likely to have a worse outcome?).
Thanks,
Joe S.
Thanks for analyzing this news.
It is encouraging to see development of a drug which tarceva-like therapeutic effect on smokers/former smokers.
Just studied the information about the drug: it seems only to be available as IV infusion. Although it only takes a few minutes – but is it not supposed to be taken until progression? That would mean that a patient would need an IV infusion every other week for maybe years. Is that really so?
Isn’t Alimta currently the preferred first-line agent (combined with a platinum doublet) for NSCLC – adenocarcinoma patients (smokers and non-smikers alike)? And, if so, is Fotolyn then not advisable as an second or third line agent later on (whether in a clinical trial setting or not)?
I don’t want to get too far ahead of the data. I don’t think I’d take these data as the definitive word on the subject yet. First, the entire trial only had 200 patients, and fewer still available in the survival analysis. When you look just at the subset on Alimta, you’ve got perhaps a few dozen (exact number wasn’t reported). I think it’s premature to start developing theories and treatment guidelines based on a conclusion that may well be inaccurate. The data aren’t a strong enough base to give them that much credence.
To me, it suggests that Fotolyn is an agent that probably stacks up at least as well as Tarceva for current and former smokers, and there may be patients for whom it is meaningfully better. However, I would be wary about making more definitive statements in the absence of more information. I also think it’s not clear that these results will be enough to lead to widespread clinical use of Fotolyn in lung cancer, especially if insurance companies aren’t covering it.
kej, while I believe it is meant to be taken until progression, most people are getting treated for only weeks to months, not years. We’ll see the actual data in the future, but I’d bet good money that only a very small proportion are without progression after 6 months.
The company did the trial against Tarceva knowing that Tarceva was an easy mark in the smoker population, even if it does have some real activity. Fotolyn didn’t beat Tarceva in people with an EGFR mutation here. It edged it in a group for which there is probably a benefit that is in the decidedly modest range.
Further, all the release says (according to Dr. West’s post) is that “They saw trends in favor of Fotolyn for overall survival in all groups except those with squamous NSCLC and those who received prior Alimta (pemetrexed).” Just because a trend wasn’t seen among those few dozen patients doesn’t mean anything. Just as we should not leap to conclusions about some of the small subgroups where a trend was shown, we should NOT conclude from this that Fotolyn “doesn’t work” among those with prior Alimta. All we can say is that the few dozen patients (split then into two groups) don’t show a trend toward Fotolyn being better than Tarceva. A MUCH larger study (with planned subgroup analyses) would be needed to draw any more definitive conclusions.–Neil