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Posts tagged ‘Alimta’

Does maintenance therapy with chemotherapy improve PFS in non-squamous lung cancer?

By on June 24, 2011

In the final article on the lung cancer mini series this week, it’s time to discuss one of my least favourite topics – chemotherapy.

Regular readers will remember the guest post from Dr Al Lalani just prior to ASCO on the acronymania that pervaded the abstract book this year for various clinical trials.  I was therefore much amused to play ‘buzzword bingo’ at the meeting and see how many of his list I came across 😉

One trial in particular stood out in a session on lung cancer called PARAMOUNT.  Three years ago, I wrote about the FDA approval of pemetrexed (Alimta) in front line treatment of NSCLC in non squamous histology.

The new phase III data looked at whether it was safe and effective to continue pemetrexed as maintenance therapy after initial induction treatment with the pemetrexed plus cisplatin doublet for four cycles.  A total of 939 patients with advanced nonsquamous NSCLC were enrolled in the study.

Patients whose disease had not progressed during the induction, and had a good performance status of 0-1 (n=439), were randomized to receive either:

  1. Pemetrexed maintenance (500 mg/m2 on day one of a 21-day cycle) plus best supportive care (n=359) OR
  2. Placebo plus best supportive care (n=180) until disease progression.

All patients received vitamin B12, folic acid and dexamethasone. The main goal of the trial was to determine if progression-free survival (PFS) was improved by maintenance therapy with pemetrexed.

The final analysis demonstrated that the primary endpoint was met:

  1. Median PFS of 3.9 months (95% CI: 3.0-4.2) in the pemetrexed arm versus 2.6 months (95% CI: 2.2-2.9) in the placebo arm.
  2. In addition, disease control rate (% patients with response/stable disease) was 71.8% in the pemetrexed group and 59.6% in the placebo arm (P=0.009).

Toxicities were in line with those expected for pemetrexed based on previous studies, ie anemia, fatigue and neutropenia were all greater than placebo.  Discontinuations due to AEs were 5.3% with ALIMTA and 3.3% with placebo.

Overall, when considering the question of whether pemetrexed improves PFS as maintenance therapy for non-squamous NSCLC patients, it looks to be a safe and viable option, albeit with a small additional increase of 1.3 months in survival.

 

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#AACR Personalized therapy in lung cancer – part 3

By on January 19, 2010

After writing the first two posts in the series, I was much amused to see this tweet in my Twitter stream from one of buddies:

Picture 155
When you've been blogging on science, marketing, PR and cancer topics for several years you begin to wonder if it actually beneficial to anyone, so today's post is dedicated to Miguel in Barcelona for making me smile :-).  If you're on Twitter, please do follow him because he's a great guy and shares a lot of very interesting pharma related links.  Give him some Twitter love!

Today's topic is about a new generation flavanoid, ASA-404, from Novartis.  Of course, under FTC guidelines, I should disclose that as many of you know, I'm a former employee and have also done consulting work for the company, but not on this particular product.

ASA-404 is an interesting agent in phase III development.  It's a vascular disrupting agent (VDA) with a tubulin dependent mechanism of agent.  Unlike taxanes, which target the microtubulin in DNA, this agent is also part anti-angiogenic agent because it selectively disrupts the tumour vasculature with both direct and indirect effects.  In simple terms, I think of it as a kind of hybrid cross between an anti-angiogenic such as bevacizumab (Avastin) and a taxane such as paclitaxel or docetaxel.

Dr Mark McKeage presentation at the AACR lung cancer meeting was focused on the phase II that has been published to date, including a publication in the British Journal of Cancer (see bottom of article). 

The drug was well tolerated in phase I trials, achieving an MTD of 3700 mg/m2.

In a phase II trial, paclitaxel and carboplatin (pc) therapy was used as the reference arm, and ASA-404 added to the standard chemotherapy in the other arm to determine if the agent added any extra benefit for newly diagnosed patients with non-small cell lung cancer (NSCLC) with either a squamous or non-squamous histology. They looked at 2 different doses of ASA-404 – 1200mg/m2 was used in the randomised comparison with carbo-tax and 1800mg/m2 with out the comparator arm but in combination as before. 36 patients were accrued into the reference pc arm, 37 in the lower dose ASA-404 arm and 31 in the higher dose ASA-404 arm.  This gave a total of 104 patients in the pooled phase II study.

Overall, similar rates of adverse events (AE's) were seen in the squamous and non-squamous patients, except for a slight increase in AE's related to blood/lymphatic effects.  No serious AE's associated with vascular effects of bleeding, hemorrhage or hemoptysis were seen.  There was an increase in hematologic toxicities (anemia, neutropenia and thrombocytopenia) but these were not significant and none rose above 20%.  There was no apparent increase in neutropenia related sepsis.

In terms of efficacy and median overall survival, McKey reported:

PCA  vs. PC

14.0 vs. 8.8 mos for 1200mg/m2

14.9                  for 1800mg/m2

Thus we can clearly see that adding ASA-404 to standard carboplatin-paclitaxel therapy improved median overall in frontline NSCLC by 5 months.

Recently, the FDA has approved several therapies in NSCLC in different histologies, due to either issues with side effects (bevacizumab and bleeding issues) or lack of efficacy (pemetrexed), while others such as erlotinib have been shown to be particularly effective in non-smoking female asians with an adenocarcinoma histology, although the approval is not based on histology.

Let's take a look at the ASA-404 histology data:

                Squamous:                Non-Squamous:          Overall:               

                PCA         PC             PCA         PC              PCA          PC

ORR (%)    40.0        14.3          31.7        25.0           34.4          22.2

One third of the patients had a squamous histology, but experienced no bleeding issues seen with VEGF agents.

While the results are higher for those with a squamous histology, there was also a trend towards higher efficacy in the non-squamous patients.  The positive results provided support and evidence for the drug's effectiveness and rationale for beginning the phase III triala, ATTRACT-1 in first line and ATTRACT-2 in second line NSCLC without restriction on histology.

To put the 5 months improvement in median OS with ASA-404 in context, I checked out the PI for other therapies.  Bevacizumab was approved on the basis of 12.3 months vs. 10.3 months, ie a 2 month improvement, while pemetrexed was approved on the basis of non-inferiority when comparing pemetrexed plus cisplatin to gemcitabine plus cisplatin (ie 10.3 months of overall survival in each arm).

The front-line trial has completed accrual and is ongoing, but the ATTRACT-2 trial for patients who have had prior chemotherapy is still enrolling.  You can find it here: ATTRACT-2.

Of course, these are early days yet and positive phase II data does not always translate to phase III success, but they are a hopeful sign of good things to come.  If the data are repeated, it will be good news for patients with NSCLC.  


ResearchBlogging.org
McKeage, M., Von Pawel, J., Reck, M., Jameson, M., Rosenthal, M., Sullivan, R., Gibbs, D., Mainwaring, P., Serke, M., Lafitte, J., Chouaid, C., Freitag, L., & Quoix, E. (2008). Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer British Journal of Cancer, 99 (12), 2006-2012 DOI: 10.1038/sj.bjc.6604808

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Alimta gets a new approval in first-line non-small cell lung cancer with specific histologies

By on October 5, 2008

This week, Lilly received approval from the U.S. Food and Drug Administration (FDA) for the use of Alimta (pemetrexed), in combination with cisplatin, in the first-line treatment of locally-advanced and metastatic non-small cell lung cancer (NSCLC), for patients with non squamous histology. Alimta is not indicated for treatment of patients with squamous cell non-small cell lung cancer.

According to the American Cancer Society, lung cancer (small cell and non-small cell) is the second most common cancer in both men (after prostate cancer) and women (after breast cancer).  It accounts for about 15% of all new cancers. During 2008, there will be about 215,020 new cases of lung cancer (114,690 among men and 100,330 among women).

Lung cancer is by far the leading cause of cancer death among both men and women. There will be an estimated 161,840 deaths from lung cancer (90,810 among men and 71,030 among women) in 2008, accounting for around 29% of all cancer deaths. More people die of lung cancer than of colon, breast, and prostate cancers combined.

LungCancer

Image courtesy of Upstate.edu

Approximately 80% to 85% of lung cancers are NSCLC rather than SCLC; there are 3 subtypes of NSCLC.  The cells in these subtypes differ in size, shape, and chemical makeup when looked at under a microscope.

Squamous cell carcinoma:

About 25% to 30% of all lung cancers are squamous cell carcinomas. They are often linked to a history of smoking and tend to be found in the middle of the lungs, near a bronchus.

Adenocarcinoma:

This subtype accounts for about 40% of lung cancers. It is usually found in the outer region of lung. People with one type of adenocarcinoma, also known as bronchioloalveolar carcinoma, tend to have a better outlook (prognosis) than
those with other types of lung cancer and tend to be non-smokers.

Large-cell (undifferentiated) carcinoma:

This subtype accounts for about 10% to 15% of lung cancers. It may appear in any part of the lung. It tends to grow and spread quickly, which can make it harder to treat effectively.

Since Alimta is approved for non-squamous cell histology this means that approx. 70% of NSCLC are eligible for treatment with the drug.

Approval in first-line advanced NSCLC for non-squamous cell histology was based on a Phase III, open-label randomized study (n=1725 patients) that evaluated Alimta plus cisplatin (AC arm) versus Gemzar (gemcitabine) plus cisplatin (GC arm). Median survival was 10.3 months in the AC arm and 10.3 months in the GC arm.  Median progression-free survival (PFS) was 4.8 and 5.1 months for the AC and GC arms, respectively.  Overall response rates were 27.1% and 24.7% for the AC and GC arms, respectively.

The impact of NSCLC histology on overall survival was also determined. Clinically relevant differences in survival according to histology were observed.  In the non-squamous cell NSCLC subgroup, the median survival was 11.0 and 10.1 months in the AC and GC groups, respectively. However, in the squamous cell histology subgroup, the median survival was 9.4 versus 10.8 months in the AC and GC groups, respectively.

This unfavorable effect on overall survival associated with squamous cell histology observed with Alimta was also noted in a retrospective analysis of the single-agent trial of Alimta versus Taxotere (docetaxel) in patients with stage III/IV NSCLC after prior
chemotherapy.

Patients treated with the Alimta regimen had less hematologic toxicity, fewer blood transfusions and decreased use of growth factors compared to those treated with the GEMZAR regimen. The most common adverse reactions (incidence greater than or equal to 20%) for Alimta in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia and constipation.

The main benefit from this trial is potentially a change in the treatment paradigm, because Alimta offers the first sign of activity of a drug in the maintenance setting in lung cancer.   Although there is not yet full survival data from this trial, there is a significant benefit in PFS.  Alimta can be administered over a prolonged period without cumulative toxicity, so it may allow the disease to be treated as a ‘chronic’ condition.  If that is found to be the case, then it represents a major step forward in the treatment of patients who have non-squamous NSCLC.

 

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