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Carbo/Alimta: Poised to Become a Popular First Line Doublet in NSCLC

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With last week’s FDA approval of alimta in the first line setting for NSCLC, we’re likely to see a lot of alimta (pemetrexed) use shift from the second and third line setting to first line. Alimta’s been a very popular choice for previously treated patients, based on issues like the relatively convenient schedule of a ten minute infusion one day every three weeks, no hair loss, and typically less of a drop in blood counts than seen with some other regimens. In the last year, we’ve seen a growing amount of data using it in combination with either cisplatin or carboplatin in the first line setting. While the official approval of alimta was with cisplatin and only in patients with non-squamous cancers (see prior post), I suspect that it’ll be the carbo/alimta combination that really makes an impact. Historically, US-based oncologists and their patients have preferred carboplatin for it’s easier side effect profile and greater convenience (cisplatin is usually given with loads of fluids to protect the kidneys, leading to long days in the outpatient infusion center or an overnight hospitalization stay). And based on the responses I saw on a recent audience response system for a case-based lung cancer meeting this weekend, the greater interest will again be with carboplatin instead of cisplatin.

So what data do we have to support this combination in lung cancer? Early safety and efficacy studies were done in Italy (article here) and at MD Anderson Cancer Center in Houston (article here) and were certainly encouraging. A friend of mine at MD Anderson, Dr. Ralph Zinner, led their trial and raved about how well tolerated the regimen was, with some patients continuing without progression for 8 or 10 or even more cycles. With a median overall survival of over 13 months, these results were favorable (we expect most trials from MD Anderson to exceed the numbers seen for trials around the country, due to selection bias in the population who come there), but a special appeal was the tolerability of the regimen.

At ASCO 2007, a Norwegian phase III trial was presented that compared carbo/alimta to carbo/gemcitabine (abstract here). Not surprisingly, the two doublets had a remarkably similar median overall survival, and they also had a pretty much identical quality of life over the course of treatment.

In terms of side effect profile, carbo/alimta was a modest winner, based on less significant drops in blood counts and need for transfusion support, but I’d consider the carbo/gemcitabine regimen to also be among the quite well tolerated (mostly drops in blood counts, compared with nausea or hair loss or other directly experienced side effects). Here’s the basically superimposed survival curves:

Carbo Alimta OS

Frankly, a median survival of just over 7 months is very average, certainly not exceptional. They did include patients with a marginal performance status, who accounted for nearly a quarter of the study population, so this may have contributed, since most of the historical trials included few or no patients with a performance status of two. The other issue is that this study was conducted in Europe, where second and later line treatments are not routinely administered, so patients may have done a little worse than they would have if more had received subsequent treatment.

One other issue in current clinical decision-making is that avastin is standardly combined with chemo for the subset of patients who are eligible to receive avastin. While the decisive trial that led to the approval of avastin used carbo/taxol (abstract here), many oncologists are inclined to add it to whatever chemo regimen they’d prefer to use. We received some actual evidence on the safety and efficacy of a combination of carbo/alimta/avastin in a phase II clinical trial that was presented at ASCO this year (abstract here). My friend Jyoti Patel at Northwestern led this trial of 51 patients who received 6 cycles of carbo/alimta/avastin, then switched to alimta and avastin if they hadn’t progressed:

Patel Carbo/Alimta/Avastin

With a median survival over a year, that’s very encouraging, although it’s not a large enough study to presume those numbers would be achieved in a broader population.

To me, one of the main concerns I’d have about using alimta first line is that it’s an effective and quite tolerable second or third line option, when the list of good choices is short. Perhaps transitioning from doublet to single agent alimta or alimta/avastin after 4-6 cycles of platinum-based chemo is an attractive option — several new trials are building this into their treatment plan. In the meantime, cisplatin or carbo with alimta is likely to be an increasingly used option, although the evidence would support only using it in the 70-75% of patients who have non-squamous NSCLC.


6 Responses to Carbo/Alimta: Poised to Become a Popular First Line Doublet in NSCLC

  • melissa says:

    Dr. West,

    I have an Alimta related question. After CT showed cancer progression in late August, my husband had his 1st Alimta infusion on Sept 16th. In the past three weeks, his symptom – difficulty swallow is getter modest worse. Another symptom, pain, seems the same. My questions are:

    1) does this indicate Alimta not working? If it works (shrinking tumor), shall we expect to see the benefit now (three weeks after 1st infusion)?
    2) He coughed up two brown color stuff this morning. The CT scan we had about 40 days ago showed no major problem with the lung. The last chemo Carbo/Taxol plus radiation took care of lung cavity and a lot of other tumors. What could be the cause for coughing up blood? He is on blood thinner drug right now. Is it dangerous to cough up blood while on blood thinner?
    3) His oncologist suggested dilate to ease difficulty swallow. My concern is that it just a temporary relief. The cancer soft tissue will continue to press esophagus. Do you have other suggestions?
    4) He feels stuffed and full all the time and doesn’t want to eat. The last CT scan shows soft tissue on superior mediastinal and upper abdominal adenopathy. Can these findings cause fullness feeling? Is there anything we can do to ease the symptom so he can take more nutrition? Because of swallowing problem, he is pretty much on “Ensure” diet right now.

    I know I asked you a lot of questions. As always, thank you for your help.

    Melissa

  • Dr. West says:

    Melissa,

    Although I’d always prefer to see symptoms improve rapidly, we sometimes see a dissociation between symptoms and scans. Sometimes the scans show improvement but the patient isn’t feeling well (perhaps from treatment-related symptoms), and sometimes the patient reports feeling well but the scan looks worse (subclinical progression and/or placebo effect). I also think three weeks is early to draw any conclusions except to that it’s probably not miraculously beneficial, but modest radiographic improvement could occur despite a lack of any appreciable symptomatic improvement. We usually check scans after 6-8 weeks because we expect it’s going to take at least that long to really get a read on what’s changing.

    It’s never good to cough up blood, and being on blood thinners only increases the risk, so it’s worth keeping in touch with his oncologist and keeping track of whether things are getting worse. His doctor may recommend checking his blood or stopping his blood thinner.

    Esophageal dilation is a reasonable thing. Sometimes a gastroenterologist (GI specialist) can put in a stent to prop open the esophagus. Obviously, the best situation would be to shrink the nodes compressing the esophagus, which might happen if the chemo works. Another more direct approach could be to radiate the mid-chest to shrink the enlarged lymph nodes, but that is probably only feasible if that area hasn’t been radiated before.

    I do think that the disease around the stomach could be limiting how much it will expand, but other than taking more frequent small meals, I don’t have much beyond that to suggest.

    Good luck.

    -Dr. West

  • melissa says:

    Dr. West,

    Thank you so much for your quick response. He started to have vomiting yesterday and he vomited once again today. Also, he started to feel extreme fatigue on Sat. I was hoping these are chemo side effect snot the cancer in stomach or stomach lining etc. Have you had patient reporting fatigue and occasional vomiting three weeks after Alimta? He felt fine in the fist two weeks after Alimta infusion. He didn’t feel anything with Carbo/Taxol.

    Thanks.

    Melissa

  • Dr. West says:

    No, I really doubt that chemo effects would occur 2+ weeks after the chemo, except for decreased blood counts. I think nausea and fatigue worse after 2 weeks is particularly after alimta.

    -Dr. West

  • joshus22 says:

    Dear Dr. West,

    I am a new reader in the web. However, I have learned a lot of important information for my wife from the web, particularly from your posts. My wife (middle of 40s) was finally diagnosed with lung cancer at Stage IIIB on Jan. 21, 2010. Right lung was found out with a lot of lung effusion.
    Symptoms: cough for more than one and half months , short breath, and less energy.
    FINAL DIAGNOSIS: Positive for malignancy with features of non-oat cell carcinoma, favor poorly differentiated adenocarcinoma with immunophenotype indicating origin from a pulmonary primary. The CT showed a 4.3 cm tumor in right lung.
    Other tests: MRI and PET/CT showed other body parts with negative except right lung.
    Biopsy diagnosis summary (02/23/2010): Metastatic adenocarcinoma.

    The DNA analysis was conducted with several gene mutation analysis.
    IHC report: EGFR H score: 300 (100%@3+)
    No other gene mutation was significantly matched up.

    Caring Status: We have made our mind strongly that we will face it, and help my wife to beat the beast, and overcome the “crisis”.

    My wife had a VATS Pleurodesis surgery in late of January to help her lung function after draining lung fluid.
    Dr. suggestions: two cycles of chemo in next six weeks, and then take Tarceva. Following options for my wife’s treatment:
    1. Carbo/Taxol/Avastin
    2. Carbo/Taxol/1121B
    3. Carbo/Alimta/avastin

    We discussed about which option better for my wife with her doctor, and the doctor recommended third option as first line of treatment. After reading your post of “Carbo/Alimta: Poised to Become a Popular First Line Doublet in NSCLC“, my wife also prefers to taking the third option.

    Could you provide us with more opinion based on my wife situation?

    I would really appreciate your comments and suggestions.

    Best regards,

    Joshua22

  • Dr West says:

    Joshua,

    All of the options listed are completely appropriate, and there are trials being done trying to determine which of these might be better than another. There is a very significant possibility, even probability, that there are no meaningful differences in efficacy among them. Some people might well choose an Alimta-containing first line regimen because it is often particularly well tolerated and patients don’t tend to have hair loss, but it’s not possible for me to make a recommendation among three very fine choices. Besides the fact that we don’t have any good evidence to favor one over another, legally I’m not permitted to make a medical recommendation for someone who isn’t my patient.

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