he claim that the pemetrexed (Alimta, Eli Lilly) has superior efficacy in the initial treatment of advanced lung adenocarcinomas (in combination with cisplatin) is based on uncertain and perhaps even "spurious" evidence, argue two oncologists in an essay published online July 27 in JAMA Oncology.
"The claim that pemetrexed is superior in adenocarcinoma is one that is not supported by the US FDA [US Food and Drug Administration] and is not supported by a careful consideration of the evidence," said coauthor Vinay Prasad, MD, an oncologist at the Knight Cancer Institute at the Oregon Health and Sciences University in Portland, Oregon, in an email to Medscape Medical News.
Nevertheless, pemetrexed is widely perceived to offer superior efficacy by oncologists, he said.
Furthermore, all major oncology groups consider cisplatin-pemetrexed the standard of care.
For example, the National Comprehensive Cancer Network (NCCN) guidelines state: "There is superior efficacy and reduced toxicity for cisplatin/pemetrexed in patients with non-squamous histology in comparison to cisplatin/gemcitabine."
So, where did the idea of superiority come from?
The essay authors say the basis of the NCCN's and other groups' recommendation is primarily a 2008 phase 3 randomized trial that was designed to test the noninferiority of cisplatin-pemetrexed in comparison with standard cisplatin-gemcitabine in the overall population of patients with non–small cell lung cancer (NSCLC) (J Clin Oncol. 2008;26:3543-3551).
In the trial, investigators reported the same overall survival (OS) for the two treatment groups (10.3 months), which established the noninferiority of cisplatin-pemetrexed.
The investigators also assessed OS in 19 subgroups. They discovered that OS was significantly increased by 1.7 months with pemetrexed vs gemcitabine (12.6 vs 10.9 months; P = .03) among patients with nonsquamous NSCLC (of which the most common type is, by far, adenocarcinoma).
This subgroup finding was similar to a subgroup finding in a 2004 trial of pemetrexed vs docetaxel, say Dr Prasad and essay coauthor Bishal Gyawali, MD, MPH, a medical oncologist at the Institute of Cancer Policy in London, United Kingdom.
In their new essay, the pair focus on the 2008 trial, the lead author of which was Giorgio Scagliotti, MD, of the University of Torino in Italy.
Dr Prasad explained that "when you ask doctors why they think pemetrexed is better for adenocarcinoma, they invariably say the Scagliotti paper, so that is why we focused on it. Only the Scagliotti study is in the front line, where the preference for pemetrexed is strongest."
In any case, findings from subgroup analyses have limitations as evidence, say the essay authors. "Subgroup analyses should always be considered hypothesis generating and not definitive," they assert.
Subgroup analyses should always be considered hypothesis generating and not definitive. Dr Vinay Prasad and Dr Bishal Gyawali
The only way to confirm an important subgroup finding is through a replication study, which is "not likely" in the case of pemetrexed, say the essay authors, because its "market exclusivity" is winding down.
"When you find a subgroup that you think benefits ― but there remains high uncertainty (as in the case of pemetrexed) – then you need to do a confirmatory study," said Dr Prasad.
Subgroup evidence is not the only problem with the claim that pemetrexed is superior to gemcitabine, the essayists say.
In the 2008 Scagliotti study, there was no improvement in progression-free survival (PFS) among the nonsquamous NSCLC patients. "There is no reason for a drug like pemetrexed (unlike immunotherapy) to increase OS without increasing PFS," write Dr Prasad and Dr Gyawali. (In immunotherapy, there is sometimes a lag in treatment response, so a patient may experience disease progression before the drug takes effect and extends life.)
However, in an email to Medscape Medical News, Dr Scagliotti objected to the essayists' contention that pemetrexed has not been strongly proven to be effective in nonsquamous NSCLC.
"There is no doubt about the efficacy of pemetrexed-based therapy in nonsquamous, non–small cell lung cancer," he said in an email to Medscape Medical News.
There is no doubt about the efficacy of pemetrexed-based therapy in nonsquamous, non–small cell lung cancer. Giorgio Scagliotti
"Conclusions regarding the use of pemetrexed in nonsquamous patients are based on multiple studies and not one single subgroup analysis, as the authors imply," he added.
Dr Scagliotti, who is a paid consultant to Eli Lilly, pointed to a trio of phase 3 clinical trials, including his own 2008 study.
The other two studies provide "broader context," he said.
One of those studies is the above-mentioned trial comparing pemetrexed with docetaxel in the second-line setting (J Clin Oncol. 2004;22:1589-1597).
The other trial compares pemetrexed with placebo among patients receiving best supportive care for advanced NSCLC (Lancet. 2009;374:1432-1440).
"A strong, statistically significant overall survival benefit for pemetrexed in nonsquamous NSCLC was observed in all three studies," he said.
The essayists also observe that although the FDA approved pemetrexed as initial frontline therapy (with cisplatin) for locally advanced and metastatic nonsquamous NSCLC in 2008, the FDA stated that the drug lacks efficacy in cases with squamous histology, and it refrained from "stating it is superior in nonsquamous histology."
Nevertheless, the 2008 FDA approval of pemetrexed for the frontline treatment of lung cancer helped catapult it into a "blockbuster" cancer drug, the essayists observe. Previously, the drug had been approved only for the treatment of mesothelioma. Since 2008, sales have been at least $1 billion annually. In 2015, pemetrexed sales were $2.5 billion.
Dr Prasad believes pemetrexed was approved for good reasons. "I would have approved pemetrexed, as it is noninferior, has a different safety profile, and should be an option," he said.
But noninferiority and safety tend not to make for blockbuster drugs, he added.
"The belief that it is superior almost surely drove the popularity, and that belief is very uncertain and may be wrong," said Dr Prasad.
Martin Edelman, MD, a medical oncologist and chair of the Department of Hematology/Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania, disagreed about pemetrexed's appeal.
"The vast majority of physicians treating lung cancer" choose pemetrexed for nonsquamous NSCLC "based upon both its modestly superior efficacy and markedly superior tolerability," he told Medscape Medical News.
"The essay authors grudgingly state that 'many experts believe that it has a more favorable adverse effect profile,' " Dr Edelman commented. There is no need for opinion, the evidence is abundant, he suggested. Evidence presented in the Scagliotti article "demonstrates highly significant advantages for the pemetrexed arm in both hematologic and nonhematologic toxicities," he said.
Dr Edelman also repeatedly objected to the criticisms of pemetrexed by Dr Prasad and Dr Gyawali.
First, he addressed the criticism with respect to PFS. "PFS is a weak endpoint that can be quite subjective. OS has always been considered the gold standard,” he asserted.
"Interestingly, in the Scagliotti study, PFS was numerically superior for the pemetrexed-based regimen in nonsquamous patients (5.3 vs 4.7), with the reverse true in squamous patients. While nonsignificant, the trend is similar to the OS results," he pointed out.
Dr Scagliotti also addressed this issue. In the above three studies that he cited, there was a statistically significant PFS benefit was observed in two, he said. Plus, yet another phase 3 trial of continuation-maintenance pemetrexed conducted solely in nonsquamous patients also showed a statistically significant PFS benefit ( Lancet Oncol. 2012;13:247-55).
Dr Edelman also took on subgroup analyses: "I agree with the authors that one should view subgroup analyses with caution; however, this was not the correct example."
This was not the correct example. Dr Martin Edelman
Dr Edelman continued: "As opposed to most subgroup analyses, the evaluation by histology was preplanned [in the Scagliotti study]."
The essayists also "fail to mention" that the number of patients in the nonsquamous subgroup (n = 1000) was greater than in most phase 3 trials, he said.
Subgroup analyses are "legitimate," Dr Edelman added, when an overall study achieves the primary endpoint of noninferiority, which was the case with the Scagliotti article. "If the primary objective had not been met, then the [essay] authors would be correct in stating that it should be considered hypothesis generating," he commented.
Dr Edelman has acted as a paid consultant to Lilly in the past. However, he said that he has been critical of permetrexed's use as maintenance therapy in advanced lung cancer (J Thor Onc. 2012; 7:1331-36) and has presented a "skeptic's view."
He said there is "an excellent biological rationale" for the relative selectivity in nonsquamous carcinoma, based upon relative thymidylate synthase levels in nonsquamous vs squamous NSCLC.
Dr Scagliotti further commented on a number of these issues. He said that the subgroup analyses in his 2008 trial were "preplanned for the express purpose of testing a specific biological hypothesis," namely, that pemetrexed "might show differential efficacy based on the expression of its cellular target [TS]."
Because of that focus, he said that "this is exactly the opposite of a hypothesis-generating exercise!"
Costly Drugs and the Need for Better Evidence
When it was first approved for the treatment of mesothelioma, the estimated cost of pemetrexed per treatment cycle was $3900, compared to $1664 for docetaxel, according to a 2004 analysis (Nat Rev Drug Discov. 2004;3:825-826).
"Unquestionably, cost is a significant consideration," conceded Dr Edelman.
The essay authors believe a drug that costs so much more than standard care should be held to higher standards of evidence of efficacy than subgroup analyses.
"We cannot incorporate drugs as expensive as pemetrexed into our guidelines or hail them as superior in the absence of robust scientific evidence that supports those claims," write Dr Prasad and Dr Gyawali.
Dr Prasad and Dr Gyawali have disclosed no relevant financial relationships. Dr Edelman has been a paid consultant to Eli Lilly.
Jama Oncol. Published online July 27, 2017. Abstract