A very interesting NSCLC poster by LGND at ASCO reposted below. These results are pretty dramatic (although with small numbers of patients), and if they hold up would dramatically transform LGND's valuation. Recall that the drug's approved use is for an indication with a new patient population of only around 1k a year.
I've posted a current release describing four current treatments by way of comparison. This seems to be roughly the same patient population, although of course it's always dubious to compare results across different trials. It does however seem to back up the claim in the LGND trial: ``We believe our one-, two- and projected three-year survival are among the best reported in the literature,''
Anyhow, LGND was down today amidst the boom, and I bought some. Maybe we'll start getting some off-label use right away.
Tuesday May 15, 6:35 pm Eastern Time
Press Release
Targretin Capsules in Combination Therapy May Prolong Survival in Patients
with Non-Small Cell Lung Cancer
Data from Phase I-II Trials Published in The Journal of Clinical Oncology
SAN DIEGO--(BW HealthWire)--May 15, 2001--Ligand Pharmaceuticals
Incorporated (Nasdaq: LGND - news) announced today the publication of
results of Phase I-II clinical studies suggesting that Targretin®
(bexarotene) capsules administered front-line in combination with
chemotherapy may prolong survival in patients with non-small cell lung
cancer (NSCLC). These results were presented in a poster session at the
annual meeting in San Francisco of the American Society of Clinical
Oncology, and published in the May 15, 2001, issue of The Journal of
Clinical Oncology.
In the Phase I-II trial, Targretin was administered front-line in
combination with cisplatin-based chemotherapy to 43 patients with Stage IIIb
pleural effusion and Stage IV NSCLC. In Phase I, Targretin dosage was
escalated in cohorts of three to six patients from 150 mg/m2/day through 600
mg/m2/day, starting one week prior to introduction of chemotherapy. Phase II
was initiated when the optimal dosage was determined to be 400 mg/m2/day.
Eight of 43 patients in the Phase I-II trial had major responses, with 7 of
28 responses occurring at 400 mg/m2/day. At this dose, median survival was
14 months, with 7 of 28 patients still alive after 28 months of monitoring.
One-year survival was 61 percent, two-year survival was 28 percent. In
contrast, results from a recently reported large-scale, randomized Eastern
Cooperative Oncology Group study (ECOG 1594) indicate the median survival of
late-stage NSCLC patients treated with any one of four leading combination
chemotherapy regimens with two agents is approximately eight months, and
only approximately one-third of these patients survive one year.
Adverse events included asthenia, nausea, hyperlipemia, vomiting, headache,
exfoliative dermatitis, and anorexia.
``We believe our one-, two- and projected three-year survival are among the
best reported in the literature,'' said Fadlo R. Khuri, M.D., Assistant
Professor of Medicine, Assistant Internist, and Director of Educational
Programs, Department of Thoracic Head and Neck Medical Oncology at the
University of Texas M.D. Anderson Cancer Center, and lead investigator.
``While this is a Phase II trial with a limited number of patients, these
survival data are clinically important and exciting.''
The poster, entitled ``Phase I-II Trial of Bexarotene (Targretin®) with
Chemotherapy for Chemo-Naive Patients with Advanced Non-Small Cell Lung
Cancer,'' was presented today by Dr. Khuri. Other authors include Drs. Rigas
(Dartmouth Hitchcock Medical Center), Figlin (UCLA Jonsson Comprehensive
Cancer Center), Gralla (Ochsner Clinic), Reich (Ligand Pharmaceuticals
Inc.), and Hong (MD Anderson Cancer Center).
Targretin Capsules NSCLC Registration Program
Ligand plans to conduct two randomized Phase III trials of approximately 600
patients each. The positive efficacy results of this Phase I-II trial and
the manageable toxicity profile of the combination therapy allow Ligand to
proceed directly to a Phase III trial to evaluate the benefits of adding
Targretin capsules at 400 mg/m2/day to a chemotherapy regimen of cisplatin
and vinorelbine in direct comparison to the chemotherapeutic regimen alone.
Ligand expects to begin accruing patients during the second quarter 2001.
The second trial of similar design will study Targretin capsules in
combination with carboplatin and paclitaxel and is expected to commence by
year end.
Non-Small Cell Lung Cancer
Lung cancer is the leading cause of cancer death for both men and women. The
American Cancer Society estimates that 164,100 Americans will be diagnosed
with lung cancer in 2001; of those, 131,200, or approximately 80 percent,
will be diagnosed with NSCLC. Early-stage NSCLC is usually treated with
surgery or radiation, sometimes combined with chemotherapy. Late-stage NSCLC
is usually treated with radiation and/or combination chemotherapy regimens.
Targretin Capsules
Targretin capsules received U.S. Food and Drug Administration (FDA) approval
in December 1999 for the treatment of cutaneous manifestations of cutaneous
T-cell lymphoma (CTCL) in patients who are refractory to at least one prior
systemic therapy. The European Commission granted marketing authorization
for Targretin capsules in April 2001. In the U.S., Ligand currently markets
its approved products, Targretin capsules, Targretin gel, ONTAK® and
Panretin® gel, through its specialty oncology and dermatology sales forces.
In Europe, Ligand has marketing and distribution agreements with Ferrer
Internacional SA, Alfa Wassermann, S.p.A, and Elan Pharma International,
Ltd.
Wednesday May 16, 1:39 pm Eastern Time
Press Release
SOURCE: GlaxoSmithKline
Phase II Randomized Study Compares Four Regimens For Advanced Non-Small Cell Lung Cancer
- Combination of Navelbine(R) (Vinorelbine Tartrate) Injection and Gemcitabine Results Suggests Efficacy Similar to Platinum-Based Regimens -
RESEARCH TRIANGLE PARK, N.C., May 16 /PRNewswire/ -- At the annual meeting of the American Society of Clinical Oncology, a four-arm phase II trial in advanced non-small cell lung cancer (NSCLC) suggested that the combination of Navelbine® (vinorelbine tartrate) and gemcitabine produced a numerically higher median survival time than the other three arms evaluated, including the other non-platinum doublet of paclitaxel/gemcitabine (10.7 months versus 8.7 months, respectively).
``Using the newer, and often less toxic chemotherapy drugs in combination will likely be a trend for the future of lung cancer treatment,'' said John D. Hainsworth, M.D., director of clinical research at the Sarah Cannon Cancer Center in Nashville, Tennessee and one of the study's investigators. ``For nearly 20 years a standard treatment for advanced lung cancer has included NSCLC accounts for approximately 80% of lung cancer cases and most patients (70%) have advanced, inoperable cancer (referred to as stage III or IV disease). In these patients, a cure is rare and most die one to two years after diagnosis. NSCLC is the leading cause of cancer-related death in both men and women.(i)
The multi-center phase II study compared four different third generation chemotherapy regimens randomized among 267 patients with stage IIIB and IV NSCLC: two triplets that included a platinum-based drug (carboplatin/paclitaxel/gemcitabine, and carboplatin/paclitaxel/vinorelbine); and two doublets without a platinum compound (vinorelbine/gemcitabine, and paclitaxel/gemcitabine). The study was designed to compare the toxicities, response rates, and progression-free interval of the four arms.
According to the reported results (See Tables 1 and 2), the regimen with vinorelbine and gemcitabine appeared to cause less grade 2/3 neurotoxicity, nausea/vomiting, and diarrhea, and less grade 3/4 myalgia/arthralgia, anemia and thrombocytopenia (a decrease in the number of blood platelets) than the three other combination therapies. The patients in the group using vinorelbine and gemcitabine experienced no severe alopecia (hair loss) and 25% of these patients had mild hair thinning. One hundred percent (100%) of the patients in the other three study arms had severe hair loss.
Although the study was not large enough to show any statistically significant differences in response rates and progression-free survival, the median survival of the arm using vinorelbine in combination with gemcitabine (10.7 months) was reportedly longer than the other three regimens: carboplatin/paclitaxel/gemcitabine, 9.6 months; carboplatin/paclitaxel/vinorelbine, 9.9 months; and paclitaxel/gemcitabine: 8.7 months. In addition, the progression-free survival in the study arms using doublets (vinorelbine/gemcitabine and paclitaxel/gemcitabine) appears to be longer than the platinum-containing triplet regimens (6.6 months versus 5.4 months for carboplatin/paclitaxel/gemcitabine and 4.9 months for carboplatin/paclitaxel/vinorelbine).
The investigators concluded that the third generation doublet regimens may be less toxic and as efficacious as the third generation triplet regimens. ``We really are trying to find the best treatment available for advanced lung cancer,'' said Dr. Hainsworth. ``This study may lead us to new options that are as effective, but better tolerated.'' Dr. Hainsworth is participating in a follow up randomized phase III study to compare vinorelbine in combination with gemcitabine with the combination of carboplatin/paclitaxel/gemcitabine.
Navelbine, which is available in the United States from GlaxoSmithKline, is not indicated in combination with gemcitabine. Navelbine Injection is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with inoperable, advanced NSCLC. In clinical trials to date, granulocytopenia is the major dose-limiting toxicity with Navelbine, although it has been generally reversible and not cumulative over time.
Administration of Navelbine is contraindicated in patients with pretreatment granulocyte counts of < 1000 cells/mm3. Patients treated with Navelbine should be frequently monitored for myelosuppression during and after therapy. In North American clinical trials with single-agent Navelbine, nonhematologic toxicities were usually mild or moderate and included injection-site reactions (38%), nausea (34%), vomiting (15%), constipation (29%), fatigue (27%), peripheral neuropathy (20%), diarrhea (13%), and alopecia (12%).
GlaxoSmithKline, one of the world's leading research-based pharmaceutical and health care companies, is committed to improving the quality of human life by enabling people to do more, feel better and live longer.
GlaxoSmithKline is committed to the research, development, manufacturing and marketing of therapeutic and supportive care products for hematology and oncology patients. Currently, GlaxoSmithKline markets Zofran® (ondansetron HCl), Hycamtin® (topotecan hydrochloride), Navelbine® (vinorelbine tartrate) Injection, Argatroban Injection, Alkeran® (melphalan), Leukeran® (chlorambucil), Compazine® (prochlorperazine), Purinethol® (mercaptopurine), Myleran® (busulfan), and Thioguanine. GlaxoSmithKline has novel agents in late-stage development, including a radioimmunotherapy Bexxar (tositumomab and iodine 131 tositumomab). Full prescribing information for all GlaxoSmithKline products is available upon request or on the company web site.
Table 1
Arm A - Paclitaxel, Carboplatin, Gemcitabine (PCG)
Arm B - Paclitaxel, Carboplatin, Vinorelbine (PCV)
Arm C - Paclitaxel, Gemcitabine (PG)
Arm D - Gemcitabine, Vinorelbine (GV)
Hematologic
Toxicity Arm A Arm B Arm C Arm D
(Grade 3, 4) (PCG) (PCV) (PG) (GV)
(Percent
of courses)
Leukopenia 21% (31 pts) 36% (41 pts) 9% (11 pts) 14% (20 pts)
(A to B p=.01) (B to C p=.01)
(A to C p=.04) (B to D p=.04)
Anemia 5% 4% 4% 2%
Thrombocytopenia 17% (30 pts) 3% (3 pts) 3% (8 pts) 1% (2 pts)
(B to A p=.04) (C to A p=.04)(D to A p=.01)
Hospitalizations 1% (3 pts) 10% (16 pts) 2% (6 pts) 2% (4 pts)
for neutropenia/
fever
Platelet
transfusions 4% (8 pts) 1% (2 pts) 0.5% (1 pt) 0%
RBC transfusions 11%(20 pts) 5% (12 pts) 5% (8 pts) 5% (9 pts)
(A to All p=.04)
Cytokines given 32% 31% 25% 20%
Septic death 1 pt 1 pt 2 pts 1 pt
Table 2
Arm A - Paclitaxel, Carboplatin, Gemcitabine (PCG)
Arm B - Paclitaxel, Carboplatin, Vinorelbine (PCV)
Arm C - Paclitaxel, Gemcitabine (PG)
Arm D - Gemcitabine, Vinorelbine (GV)
Non-hematologic Arm A Arm B Arm C Arm D
Toxicity (PCG) (PCV) (PG) (GV)
(Percent of
courses)
Neuropathy 10% (22 pts) 21% (32 pts) 10% (13 pts) 4% (9 pts)
grade 2-4 (D to B p=.04)
Alopecia
grade 1 0% 0% 0% 25%
grade 2 100% 100% 100% 0%
Nausea/vomiting 6% (16 pts) 5% (12 pts) 8% (16 pts) 2% (6 pts)
grade 2/3
Diarrhea 5% (9 pts) 2% (5 pts) 3% (7pts) 1% (2 pts)
grade 2/3
Myalgia/
arthralgia 14% (28 pts) 20% (39 pts) 19% (27 pts) 7% (12 pts)
grade 3/4 (D to C p=.05)
(D to B p=.02)
(D to A p=.01)
(i) Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In:
DeVita Vt, ed. Cancer: Principles and Practice of Oncology. 5th
edition, Philadelphia, PA. Lippincott-Raven Publishers 1997;
pages 858-911. |
