This year’s ASCO was packed with promising early stage trials, but very few positive late stage trials with an impact on medical practice. The two most important practice changing trials were phase III studies for Eli Lilly’s (LLY) Alimta and Roche’s (RHHBY.PK) Herceptin. These drugs are likely to enjoy a boost in revenues starting from next year, as both demonstrated impressive survival prolongation in lung and gastric cancer patients, respectively. The studies also underscore the paradigm shift in the industry towards personalized medicine, where a drug is given only to patients who have a high likelihood of deriving benefit. This article will focus on Alimta, which was, in my opinion the winner of ASCO 2009.
A new treatment line
Alimta was evaluated as maintenance therapy in Non small cell lung cancer (NSCLC), the largest oncology market. Maintenance therapy is a new treatment modality in which patients receive additional treatment straight after first line chemotherapy. Traditionally, patients receive first line treatment and are then re-treated with second line therapy only after the disease progresses or recurs. Some hope that slotting an additional treatment even before disease progression could benefit some, if not most patients. The concept of maintenance therapy for NSCLC has already been validated in previous trials, which created a lot of enthusiasm as well as controversy around this strategy.
Going into ASCO, a lot of attention was given to OSI’s (OSIP) and Roche’s Tarceva, which was evaluated in two studies as maintenance therapy for NSCLC. There was a great deal of enthusiasm towards Tarceva as maintenance therapy because it had two features which are considered ideal for this setting: It is an oral drug and it leads to relatively few side effects.
Although the Tarceva trials were technically successful, they turned out to be quite disappointing. Tarceva had a dramatic benefit in a subset of patients which comprises ~10% of the overall patient population, but showed a very modest gain in the general patient population. As a result, it seems that Tarceva, which is already approved for second line treatment will be used only for a minority of patients in the maintenance setting.
Luckily, Lilly’s Alimta more than compensated with an impressive data set in the same setting.
The Alimta study
The Alimta trial included 663 patients who were randomized to receive Alimta or placebo right after standard first line therapy. The trial was already presented at last year’s ASCO and showed encouraging results in terms of delaying disease progression. This year, investigators presented an update from the study, which included overall survival. Alimta increased survival by 2.8 months, which is fairly impressive given the typical survival of about a year for these patients.
However, Alimta seemed ineffective and even detrimental in a subset of patients with a specific tumor subtype called squamous NSCLC. A similar trend was also observed in previous trials with Alimta, and as a result, patients with squamous disease, who represent about a third of the NSCLC market, are not eligible for Alimta at any stage.
Supposedly, this should have a negative effect on Alimta, which instantly saw its addressable market shrink by ~30%. Other drugs for late stage NSCLC such as Tarceva and Taxotere are approved for all NSCLC patients. But the analysis also showed that in the remaining two thirds of patients, Alimta had an overwhelming benefit. The difference in activity between the two subsets mirrors data from two previously reported trials which led to the approval of Alimta in the first and second line settings. In both of these studies, Alimta proved superior to other chemo agents only in non-squamous patients.
In the recent maintenance study, non-squamous patients who received Alimta had a median survival of 15.5 months compared to 10.3 months for the placebo arm. A survival difference of over five months is unprecedented in NSCLC, far better than any other therapy has managed to achieve in this patient population. To put things in perspective, Avastin was approved based on a survival increase of 2 months to just over one year in a similar patient population. As expected, squamous patients who received Alimta did not gain anything and even did worse than patients on the placebo arm.
There was a minimal difference between squamous and non-squamous patients in the placebo arm, which is in bright contrast to the strong difference in the Alimta arm. This further validates the assumption that the survival improvement in the non-squamous group is derived solely from Alimta. Finally, it is important to note that the subset analysis was not a retrospective attempt to make the data look more compelling, but a pre-planned analysis that relied on prior findings.
There are now results from three large randomized trials which evaluated Alimta as first line, second line and maintenance therapy, indicating that Alimta is highly active in non-squamous patients. The striking survival difference at ASCO coupled with previous trials will probably make Alimta a preferred drug for non-squamous patients. The exclusion of squamous patients, who account for a third of the market, decreased Alimta’s market potential but it also strengthened the drug’s position in the rest of the market.
Alimta’s market potential
Alimta competes with some of the biggest oncology brands including Taxotere, Gemzar Tarceva and Avastin. However, because each patient may receive more than one treatment line and potentially, a combination of two or more agents, it is not necessarily a zero sum game. Physicians might, for example, start treating patients with a standard platinum regimen, add Alimta as maintenance therapy right afterwards and put the patient on Tarceva as second line therapy.
Due to disease symptoms and drug related side effects, only half of the patients who receive first line treatment carry on to receive second line therapy, with an even smaller portion receiving third line treatment. Therefore, earlier treatment lines represent a larger commercial opportunity. The maintenance setting also represents a smaller opportunity than that of first line setting, as only patients who achieve clinical response or disease stabilization are eligible (~55% of first line patients).
Every year, about 100 thousand patients in the US receive upfront therapy for advanced NSCLC. Alimta could be used only in non-squamous patients, leaving approximately 67 thousand patients as candidates for the drug. The addition of maintenance and second line therapies creates a combined opportunity of roughly the same size. Physicians might use the same drug in the first line and as maintenance treatment but they rarely use the same drug in both first and second line NSCLC. This brings Alimta’s market potential to approximately 100 thousand “treatments” per year. Using an average price of $20,000 per treatment, Alimta’s market potential in the US alone is $2B.
Gaining market share in a crowded market
The NSCLC market is one of the most crowded oncology markets. Ten years ago, all patients were treated the same with a limited number of drugs and treatment lines. Today, not only are there more approved drugs and treatment lines, investigators have identified many factors that guide which therapies should be used for every patient. These factors include genetic mutations, protein expression levels and other parameters such as stage, age, price, compliance and tolerability of side effects.
Approximately ~10% of patients have an EGFR mutation, rendering them highly responsive to Tarceva. For these patients, Tarceva will probably be chosen in the maintenance setting or even as a first line treatment, but Alimta will likely be used as a second line treatment since these patients are almost always non-squamous. In another group who have KRAS mutation (~20% of patients), Tarceva is not effective, so Alimta will probably have an advantage in this subset.
A potential barrier for Alimta’s use in the maintenance setting is Avastin, which is approved for the majority of non-squamous patients. Avastin is used in combination with first line chemotherapy and in many cases physicians use it as maintenance therapy although there is no concrete evidence that patients derive benefit from maintenance Avastin. Alimta is a chemo drug, so it usually leads to more severe side effects than Avastin, but it is also cheaper and probably more effective as maintenance therapy. Moreover, Alimta might have a clear advantage in patients who cough up blood or are on blood thinners, as they cannot receive Avastin due to safety issues.
Tarceva and Avastin are better tolerated than Alimta, but paradoxically, this could boost Alimta’s share in the first line and maintenance settings. Physicians know they can always give Tarceva, which is well tolerated even by frail patients, so they might prefer Alimta in the maintenance setting. If physicians choose Avastin as a first line treatment (Avastin is not approved for second line), they may combine it with Alimta, due to its proven ability to prolong survival. Nevertheless, Alimta and Avastin are not approved in combination as maintenance therapy, despite promising results from smaller trials.
In summary, Alimta, which started as a “me too” drug for all patients is becoming a “must have” drug for the majority of patients. The importance of the Alimta study is twofold. First, it proves that Alimta is highly effective in non-squamous patients which account for two thirds of the market. Second, it opens up a new market for Alimta, thus increasing market potential and the likelihood of using the drug throughout the continuum of care. The unique activity profile may enable Lilly to grow Alimta sales from $1.15B in 2008 to over $2.5B in 2012.
The Biotech Portfoio as of June 14th, 2009