Staff Writer

After last month's teaser in which OSI Pharmaceuticals Inc. and partner Genentech Inc./Roche AG revealed their EGFR-inhibitor Tarceva (erlotinib) had shown a significant survival benefit in its Phase III lung cancer maintenance trial, the details are on the table, allowing inevitable comparisons to Eli Lilly and Co.'s chemotherapy drug Alimta (pemetrexed).

Last month, Alimta earned the FDA's first-ever approval for the maintenance treatment of lung cancer. The standard of care is to give first-line chemotherapy or Genentech's VEGF-inhibitor Avastin (bevacizumab), wait for the tumor to progress and then give second-line Alimta or Tarceva. Following first-line treatment directly with maintenance drugs is a relatively new concept.

Alimta, already approved in first- and second-line nonsquamous lung cancer, gained its maintenance approval based on a Phase III trial in which overall survival was 13.4 months vs. 10.6 months for placebo (p = 0.012, hazard ratio = 0.79), while progression-free survival was 4.3 months vs. 2.6 months for placebo (p < 0.0001, hazard ratio = 0.50).

Top-line data from Tarceva's Phase III maintenance trial, dubbed SATURN, had investors worried that the drug might not be able to compete with Alimta. Progression-free survival was 12.3 weeks (3.07 months) for Tarceva vs. 11.1 weeks (2.78 months) for placebo (p < 0.0001, hazard ratio = 0.71). (See BioWorld Today, Nov. 10, 2008.)

But the new overall survival data, presented at the World Conference on Lung Cancer, narrowed the "apparent efficacy gap" seen in progress-free survival, Leerink Swann analyst Howard Liang wrote in a research note. Overall survival was 12 months for Tarceva vs. 11 months placebo (p = 0.0088, hazard ratio = 0.81).

Liang called Tarceva's hazard ratio "comparable" to Alimta's and noted that the median overall survival figure was "not representative of the drug's benefit" because the separation of the overall survival curves continued after the median point.

OSI's CEO Colin Goddard agreed that the Alimta and Tarceva data look "quite comparable in terms of overall benefit," although he noted that it is always difficult to compare between separate trials.

OSI plans to add the new survival data to its supplemental new drug application for Tarceva in lung cancer maintenance, which was submitted March 17 and has an action date of Jan. 18, 2010. If approved, lung cancer doctors will have two "pretty good" maintenance options, Liang said, adding that each drug will be best for certain patients.

Alimta is only approved for nonsquamous patients, who make up about 75 percent of the U.S. lung cancer population. In this group, Alimta has the edge, with Phase III subgroup data showing overall survival of 15.5 months vs. 10.4 months for placebo (p = 0.002, hazard ratio = 0.70). Oppenheimer & Co. Inc. analyst Bret Holley also pointed out in a research note that Alimta will be helped by its first-mover advantage, although like many analysts, he predicts lung cancer doctors will be slow to adopt any maintenance therapy.

Tarceva, which is not limited by histology, will provide an option for the smaller subgroup of squamous patients. Additionally, doctors may choose it for maintenance in patients already receiving first-line Avastin, based on data from the Phase III ATLAS study, which was stopped early when an interim analysis showed adding Tarceva to Avastin was better than Avastin alone. (See BioWorld Today, Feb. 4, 2009.)

Tarceva also may turn out to be the treatment of choice for lung cancer patients with epidermal growth factor receptor (EGFR) mutations. Data from the SATURN trial showed that median overall survival hadn't been reached for this subgroup, and the hazard ratio for progression-free survival was 0.10 (p < 0.0001).

A hazard ratio like that in a lung cancer trial is "to my knowledge, unprecedented," Goddard told BioWorld Today. He added that this was the first time EGFR analyses had been utilized prospectively in a large Tarceva trial.

But the data in patients without EGFR mutations - 85 percent to 90 percent of the U.S. lung cancer population - also were pretty good. This group experienced a 30 percent improvement in survival (p-value = 0.0243, hazard ratio = 0.77).

Perhaps most importantly, the EGFR subset data may help Tarceva find a path to approval in first-line lung cancer. The drug currently is only approved in second-line, and while the maintenance application is under review, two Phase III trials in the first-line setting failed.

Now an ongoing Phase III trial is evaluating Tarceva monotherapy compared to chemotherapy in first-line lung cancer patients with EGFR mutations. Liang said good data here could be like AstraZeneca plc's Phase III IPASS study for EGFR-targeted Iressa (gefitinib), which proved that even though the drug failed to beat placebo in past studies, in the right patients (i.e. those with EGFR mutations) it beat chemotherapy.

Analyst George Farmer, of Canaccord Adams, wrote in a research note that these studies make it "unconscionable" for doctors to avoid EGFR genotyping of nonsquamous patients and to not "offer a small molecule EGFR inhibitor like Tarceva" as an up-front treatment of newly diagnosed patients with EGFR mutations.

Shares of Melville, N.Y.-based OSI (NASDAQ:OSIP) slipped 64 cents to close at $33.15 on Monday.

In other news from the World Conference on Lung Cancer:

• Abraxis BioScience Inc., of Los Angeles, reported Phase II results showing evidence of antitumor activity in advanced non-small-cell lung cancer patients receiving first-line treatment regimens of Abraxane (albumin-bound nab-paclitaxel) in combination with carboplatin. Patients who received 100 mg/m2 Abraxane weekly had higher overall response rates (48 percent) and progression-free survival times (6.2 months) compared to patients who received every three week and other weekly dosing regimens. A retrospective histologic analysis demonstrated that the combination therapy showed activity against both squamous and nonsquamous NSCLC. A Phase III study in NSCLC is ongoing.

• Boehringer Ingelheim GmbH, of Ingelheim, Germany, initiated a Phase III trial of BIBW 2992 in the first-line treatment of non-small-cell lung cancer (NSCLC) patients with EGFR mutations. BIBW 2992 is an oral, irreversible dual-inhibitor of EGFR and HER2. Two other Phase III lung cancer trials are ongoing. Phase II data presented at the conference showed the drug induced a 63 to 66 percent response rate and 97 percent disease control rate in first-line and second-line NSCLC EGFR-mutants. Boehringer also presented Phase II data showing that BIBF 1120, a VEGFR/PDGFR/FGFR inhibitor, induced median overall survival of 264 days in certain relapsed NSCLC patients.

• Cell Therapeutics Inc., of Seattle, said the Dartmouth-Hitchcock Medical Center presented data from a small non-small-cell lung cancer study showing that Opaxio (poliglumex paclitaxel) plus Alimta (pemetrexed, Eli Lilly and Co.) was well tolerated, with stable disease in nine of 12 patients and median progression-free survival of 3.3 months. Previous Phase III trials of Opaxio in non-small-cell lung cancer failed to meet their endpoints. (See BioWorld Today, May 3, 2005.)

• ImmunoGen Inc., of Waltham, Mass., presented data from two early trials of IMGN901 in recurrent small-cell lung cancer. The clinical benefit rate was 25 percent, with two objective responses and 15 of 68 patients achieving stable disease. IMGN901 consists of the cancer-cell killing agent, DM1, attached to a CD56-targeting antibody, huN901.

• Merck KGaA, of Darmstadt, Germany, presented a meta-analysis of Erbitux (cetuximab) plus chemotherapy in first-line non-small-cell lung cancer. The 2,018-patient analysis showed benefits in overall survival (p = 0.01), progression-free survival (p = 0.036) and overall response rate (p < 0.001). Last week, the European Committee for Medicinal Products for Human Use adopted a negative opinion on Erbitux for first-line NSCLC, and Merck has requested a re-examination. In the U.S., partners Eli Lilly and Co. and Bristol-Myers Squibb Co. withdrew their Erbitux FDA filing in NSCLC earlier this year.

• Oncothyreon Inc., of Seattle, presented long-term data from its failed Phase IIb trial of cancer vaccine Stimuvax in non-small-cell lung cancer. As of April, 10 of 16 patients were still alive without disease progression. Nine of the 10 patients previously had Stage IIIb NSCLC, for which Stimuvax is now in a Phase III trial partnered with Merck. The vaccine was well tolerated. Shares of Oncothyreon (NASDAQ:ONTY) jumped $1.93, or 41.7 percent, to close at $6.56 on Monday.

• SuperGen Inc., of Dublin, Calif., presented details of its Phase Ib trial with MP-470, a multitargeted kinase inhibitor and RAD51 suppressor, plus standard of care in small-cell lung cancer and neuroendocrine malignancies. The overall clinical benefit rate was 54 percent, with five of 13 patients achieving a partial response and two patients achieving stable disease.