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GRACE :: Lung Cancer

Maintenance Tarceva: Ready for Prime Time? Part 2: The ATLAS Trial

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Last week we discussed SATURN, the first of 2 recently presented trials testing the role of maintenance Tarceva (erlotinib) in advanced NSCLC patients. Today I will discuss the ATLAS trial, the last of the 4 major maintenance therapy trials (along with immediate versus delayed Taxotere (docetaxel) and maintenance Alimta (pemetrexed)). In the SATURN trial of maintenance Tarceva or placebo after 4 cycles of first-line chemotherapy, Tarceva prolonged progression-free survival (PFS) by about 1 week although the true benefit may have been more robust than that number indicates.

The ATLAS trial was of nearly identical design to the SATURN trial. Patients with advanced NSCLC were randomized after completing 4 cycles of platinum doublet chemotherapy with Avastin (bevacizumab) to either maintenance Avastin plus Tarceva or Avastin plus placebo. The goal, or primary endpoint, was to show improved PFS with the combination of Avastin and Tarceva.

ATLAS and SATURN Trial Designs

ATLAS and SATURN Trial Designs

(click on image to enlarge)

ATLAS also looks pretty similar to another recently presented phase III study, the BeTa (Bevacizumab Tarceva) trial, which randomized advanced NSCLC patients with progressive disease after first line chemotherapy to either second-line Tarceva or Tarceva plus Avastin. The BeTa trial was the first phase III trial to test the hypothesis that adding a vascular endothelial growth factor (VEGF) blocker to an epidermal growth factor receptor (EGFR) blocker had benefit. One key thing to remember about BeTa is that the primary endpoint was improved overall survival (OS), not PFS, which is usually much more difficult to prove (and most would argue more meaningful). BeTa did show a doubling of PFS with the addition of Avastin to Tarceva, but did not show a statistically significant OS benefit to the combination.

Now back to ATLAS. The BeTa trial suggested that there is some benefit in PFS to the addition of Avastin to Tarceva, so as the primary endpoint of ATLAS was increased PFS compared to Avastin alone I was not shocked when earlier this year a press release indicated that this trial had met its endpoint. The only mystery was the magnitude of the benefit.

So here it is: the median PFS for the combination was 4.76 months versus 3.75 months with Avastin alone, and this difference was statistically significant.

ATLAS Trial Progression-Free Survival

ATLAS Trial Progression-Free Survival

Again, not many people get overwhelmed by a one month improvement in PFS, but the fact that the curves stay separate throughout the duration of the study suggests that there are patients who are getting a significant benefit from Tarceva. At 3 months, 2/3 of patients on the combination arm were alive and progression-free, compared to only 53% of the Avastin alone arm. By 6 months those numbers were 40% versus 28%, still a pretty good gap.

So who were these patients that benefited from the addition of Tarceva? Well, the molecular analysis has not been presented yet, but we know that there was benefit seen in men and women, as well as in smokers and non-smokers. However, in SATURN we saw that most, but not all, of the benefit from maintenance Tarceva was seen in the EGFR mutant population. I see no reason to think this will not also be true for ATLAS.

So what conclusions can we draw from these trials of maintenance Tarceva, which had such consistent results that I dare say we can refer to them together in any argument for or against this practice? Let’s take a quick look at the chemotherapy maintenance trial results, which would get me shot in a scientific symposium but I’m going to do it here anyway.

The early versus delayed Taxotere trial showed an increased PFS with immediate/maintenance Taxotere of about 3 months, with a non-significant improvement in OS that was also about 3 months. The maintenance Alimta trial showed an improvement in PFS of about 2 months, although the OS benefit was a statistically significant 3 months (and 5 months for patients with adenocarcinoma histology). I think many people consider these clinically meaningful improvements and would consider changing their practice based on these results.

In contrast (not comparison, mind you, since comparing outcomes across different trials, with different patient populations, is fraught with problems), the maintenance Tarceva trials had 1 month or less improvements in PFS, with no overall survival results presented yet. If the OS is significantly prolonged when these results come out, please come back and taunt me for this post. But my guess is that there will NOT be an OS benefit seen in the overall population, although there probably will be in the EGFR mutant subgroup.

I believe that Tarceva is an effective therapy for patients with relapsed NSCLC, which is especially effective in patients with EGFR mutations. However, I don’t see how anyone could look at the results of SATURN or ATLAS and consider changing their practice to incorporate maintenance Tarceva based on these results. There probably is some real prolongation of PFS in this unselected population, but this magnitude of benefit would not, in my opinion, be worth the extra side-effects one gets with Tarceva versus the benefit of a treatment break. And for patients in whom you would consider maintenance therapy, you would have to look at the other maintenance trials and say that the evidence is more compelling with cytotoxic chemotherapy than with Tarceva.


10 Responses to Maintenance Tarceva: Ready for Prime Time? Part 2: The ATLAS Trial

  • Dr. Pinder says:

    Like Dr. Pennell, I would be hard-pressed to recommend maintenance Tarceva or Tarceva/Avastin to ALL patients based on the PFS data. The exception would be patients in whom I knew that an EGFR mutation was present. In these patients, I would consider and discuss early treatment with Tarceva because I think the more dramatic expected benefit outweighs the side effects. Toxicities like skin rash and diarrhea may be quite significant to a patient who has planned a well-deserved trip or family event after platinum-based chemotherapy.

  • Kathie says:

    Dr. Pennell, Thanks you so much for your understandable discussion of these options.

  • JimC says:

    Dr. Pennell and Dr. Pinder,

    Based on these trial results, would you tend to favor maintenance Tarceva for a patient with an EGFR mutation? Are there any additional factors you would take into account in making that recommendation? For instance, is there anything in the initial presentation of the disease at the time of diagnosis that would lead you to favor maintenance therapy, even in the face of response or stability after first-line chemo?

    Jim

  • Dr Pennell says:

    Jim, I think both Dr. Pinder and I would favor discussing the possibility of starting maintenance Tarceva for a patient with a known mutation (and in fact I would favor using Tarceva first-line in such a patient), but there is never a one-size-fits-all recommendation. There are many variables that come into play, such as how beaten-up the patient feels after first-line chemo and how symptomatic they were with their disease.

    For example, a totally asymptomatic patient with evidence of indolent (slow-growing) disease could potentially be watched closely off of any treatment and Tarceva started if they became symptomatic later on. While someone who has lots of disease and is still symptomatic might benefit from early Tarceva, which has a high response rate in mutation+ patients and could be expected to help rapidly.

  • Dr. Pinder says:

    I definitely favor Tarceva early in the treatment course of a patient with a known EGFR mutation. Like Dr. Pennell, I think Tarceva would be a good first-line choice for a patient with an EGFR mutation. In a patient who has received chemotherapy already, either maintenance Tarceva or early initiation of Tarceva at first sign of progression are both viable options. If I have a patient who was very symptomatic at initial diagnosis (shortness of breath, bone pain, etcetera), I am inclined to consider maintenance treatment and Tarceva would be first choice as maintenace therapy for someone with an EGFR mutation.

    -Dr. Pinder

  • vals says:

    Dr. Pennell and Dr. Pinder,

    How long would you recommend continued use of Avastin when patient is taking Tarceva and obviously has EGFR mutatation? For example, a patient NED after 4 Carbo/Taxol/Avastin (IIIB with pleural effusion) in Aug of 2007 and remains NED in Atlas Study (did not receive placebo) on 100 mg Tarceva plus Avastin q 3weeks.

    Thank you,
    Valerie

  • Dr West says:

    Sorry for not getting to your question for days — I’ve just been tied up at the lung cancer conference throughout this whole time and haven’t been able to spend enough time to get to everything as readily as usual.

    The party line is that you stay on the regimen you’ve been doing well on, but we also know that many patients can do well with tarceva alone for years at a time, raising the possibility that the avastin may just be along for the ride. I think we’d often just continue without change, but if a patient had any problems with tolerability, or even just wanted to stop, we’d consider that a good reason to hold avastin, continue tarceva, and monitor for progression. It’s just not known whether stopping avastin would shorten the interval before progression.

    -Dr. West

  • vals says:

    Dr. West

    Thank you for your response. I am in the ATLAS study and very closely monitored for BP and all the blood and urine tests but I would like, on the one hand, not to have to go for infusions every three weeks, yet on the other hand, I don’t want to change if it is working. My oncologist said I could stop Avastin if I wanted to, otherwise we’ll decide what to do after 5 years of NED (its over 2 right now). Comparing the results of ATLAS and SATURN studies might give an answer and I can wait.

    Valerie

  • Pingback: GRACE :: Lung Cancer» Blog Archive » Debating maintenance therapy for advanced NSCLC: Not accepted as the standard of care

  • rlei says:

    I am curious – for a patient who has had stable disease after 4 cycles of avastin/carbo/taxol and starting maintenance avastin, would you consider getting them tested for EGFR and possible switch them to maintenance Tarceva if they were EGFR mutant? Has anyone compared maintenance Avastin with maintenance Tarceva?

    Also I am curious what the approval of maintenance Avastin is – I looked on the Avastin website and I see it is approved for 1st line with carbo/taxol but I did not see anything about maintenance. Does that mean Avastin single-agent maintenance is still considered investigational? Avastin/Alimta combination maintenance is definitely investigational, correct?

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