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Top Anticipated Lung Cancer Presentations at ASCO 2012

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Top Anticipated Lung Cancer Presentations at ASCO 2012

May 25th, 2012 - by Dr. Jack West

http://blog.lungevity.org/2012/05/25/to ... asco-2012/

The upcoming meeting of the American Society of Clinical Oncology is the most pivotal conference in oncology. It is where most of the most significant clinical trials in cancer are presented, and therefore we always look forward to the offerings of this meeting with great anticipation. Some years are blockbusters, others largely disappointing for one cancer or another. From the perspective of lung cancer, this looks to me like an in between year, not a banner year, but with some interesting new and new treatments looking promising. As a preview, then, here are my top 5 most anticipated presentations in each of the two lung cancer tracks (one a combination of work on stage I-III NSCLC and SCLC, and the other track entirely on metastatic NSCLC), based on the recently released abstracts of the meeting. Starting with stage I-III NSCLC and SCLC, here are my top 5:

1) Prognostic and predictive effects of KRAS mutation subtype in completely resected non-small cell lung cancer (NSCLC): A LACE-bio study. Abstract # 7007

Dr. Frances Shepherd from Toronto will present an analysis of >1500 patients aggregated from several different trials of adjuvant (post-operative) chemotherapy, in which there were 300 KRAS mutations identified, of which 275 were on codon 12, 24 were on codon 13, and 1 was on codon 14. Historically, we haven’t assessed resultsas a function of individual KRAS mutations. However, this analysis demosntrates several interesting results. While patients with KRAS wild type (no mutation) had a strong trend toward better survival with adjuvant chemo, patients with a codon 12 KRAS mutation didn’t benefit from adjuvant chemo. And for patients with a mutation on codon 13, adjuvant chemotherapy was actually significantly detrimental. The investigators caution that these results are based on a relatively small number of patients with a codon 13 mutation, but this research highlights the relevance of the particular type of KRAS mutation and also provides evidence that patients with KRAS mutations in general don’t benefit from adjuvant chemotherapy, something that has been suggested from prior research that has looked at this question, but the evaluation of this question has been limited enough that it hasn’t emerged as a factor consistently used in considering whether to recommend adjuvant chemo for an individual patient or not.

2) SWOG 0802: A randomized phase II trial of weekly topotecan with and without AVE0005 (aflibercept) in patients with platinum-treated extensive-stage small cell lung cancer (E-SCLC). Abstract #7005

This Southwest Oncology Group (SWOG) trial is rather small, a randomized phase II study of just 98 patients, but it shows a difference in a progression-free survival (PFS) at three months into treatment of 26% when the anti-angiogenic agent aflibercept is added to topotecan, compared with 9% for topotecan alone. Moreover, the rate of disease control (the proportion of patients with either significant tumor shrinkage or at least stable disease) was 28% for the combination vs. 12% with topotecan alone. There wasn’t evidence of an overall survival (OS) benefit, but these results are still promising enough that I anticipate this early effort will lead to a randomized phase III trial. Given how limited our options have been, I think there will be great interest among oncologists and patients to enroll quickly and see if the results might be strong enough to lead to the availability of a new agent against SCLC.

3) Accuracy of FDG-PET to diagnose lung cancer in the ACOSOG Z4031 trial. Abstract #7008.

This was a “negative” trial that shows the results with PET to be surprisingly mediocre, but that’s still an important result to get out to the world. This research effort evaluated the capacity of PET scans to predict the probability that an apparently node-negative lung lesion was cancer, using a breakdown by maximum standard uptake value to estimate probability of cancer within one of

SUV/PET avidity Interpretation

0 (no PET avidity) not cancer

>0 and <2.5 (low avidity) likely not cancer

2.5 – 5 (avid) probably cancer

>5 (highly avid) probably cancer

Using this breakdown, the results from 682 PET scans were pretty inaccurate overall, particularly in determining which people didn’t have the disease. Many of the PET scans were “false positives” that suggested cancer when none was present; 17% of the surgeries were done for something that was ultimately found to not be cancer.

Results from the PET were more accurate for larger tumors, but the results here looked worse than in some other trials of PET scans, perhaps because PET scanning is less accurate for determining the probability of cancer in solitary nodules than for confirming the extent of a more widespread cancer.

Because we often become extremely focused on the implications of PET scans to clarify whether an abnormality on CT is cancer or not, I think we need to be aware of the limitations of PET scans in this setting.

4) The SELECT study: A multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Abstract #7010

Though it is inherently tempting to presume that someone with an EGFR mutation is going to benefit profoundly from addition of an oral EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib) or Iressa (gefitinib), it remains a very open question whether patients with an EGFR mutation are going to be well served or potentially harmed from addition of an EGFR TKI and one we field here pretty frequently. In fact, most lung cancer specialists are quite leery about recommending adjuvant EGFR TKI therapy outside of a trial setting, even for patients with an EGFR mutation. Why? Our assumptions have often been way off base, as illustrated by the surprising result showing a strong trend toward a harmful effect from Iressa on the BR.19 trial of adjuvant maintenance Iressa vs. placebo.

Dr. Joel Neal from Stanford (one of our two presenters for the upcoming webinar program on lung cancer highlights from ASCO) will be discuss the results for 36 patients with an EGFR mutation who underwent resection of a stage IA-IIIA NSCLC, received any chemo and radiation that was recommended, and then received maintenance Tarceva for up to two years. Though the two-year disease-free survival is 94% is higher than would be expected, I actually see some cautionary notes in interpreting these results too favorably. More than half of the patients had a stage I cancer, so this population may have had a lower risk of recurrence just from that. Second, nearly a third of the patients discontinued treatment before two years because of severe or just unacceptable side effects. Finally, there was a high rate of recurrence in the year after the Tarceva was discontinued (perhaps the same phenomenon seen on the BR.19 trial?). We need to learn more, and we will: he’ll present the details on Sunday, June 3rd.

5) A phase III study comparing amrubicin and cisplatin (AP) with irinotecan and cisplatin (IP) for the treatment of extended-stage small cell lung cancer (ED-SCLC): JCOG0509. Abstract #7003.

This is a Japanese randomized phase III study comparing first line cisplatin-amrubucin as an investigational approach with the current Japanese standard of cisplatin-irinotecanfor extensive disease SCLC. However, the key point is that the trial failed to show a benefit for the investigational arm with amrubicin. Disappointingly, the study it actually revealed an inferior OS with the amrubicin arm(median 18.3 vs. 15.0 months). Though this won’t help lead to amrubicin becoming available outside of Japane, it’s an important result to know: we aren’t missing out by not incorporating it in our first line therapy today (two large randomized studies done in North America have shown that cisplatin/etoposide is equivalent to cisplatin/irinotecan with fewer side effects; the results tend to be better with irinotecan in Japan probably because of genetic differences in how the drugs are metabolized by different populations).

And now, moving on to metastatic NSCLC abstracts, my top 5 most notable:

1) Phase II double-blind, randomized study of selumetinib (SEL) plus docetaxel (DOC) versus DOC plus placebo as second-line treatment for advanced KRAS mutant non-small cell lung cancer (NSCLC). Abstract #7503

KRAS mutations are the most common molecular marker in NSCLC, seen in ~20-25% of patients, but up until now, we’ve had precious little to suggest as a particularly beneficial therapy for them. Instead, much of the work on people with KRAS mutations has focused on their often disappointingly modest benefit from EGFR TKIs or standard chemotherapy.

This work is a phase III randomized trial that demonstrates an impressive 4 month improvement in OS when the oral MEK inhibitor selumitinib was added to standard Taxotere (note: Dr. Quesnelle provided a great introduction to MEK inhibitors here). I’ll be excited to relay details when this trial is presented on the afternoon of Monday, 6/4 by Dr. Pasi Janne, from the Dana Farber Cancer Institute in Boston.

2) Clinical activity and safety of anti-PD1 (BMS-936558, MDX-1106) in patients with advanced non-small-cell lung cancer (NSCLC). Abstract #7509

On Saturday, 6/2, Dr. Julie Brahmer from Johns Hopkins will present information on the early work done on the anti-PD1 immunotherapy BMS-936558, also known as MDX-1106, in patients with advanced NSCLC. The abstract notes that it’s only 10 patients being discussed, but responses lasting six months or longer have been seen in 3 of 10, and this agent has significant activity in many other cancer types as well.

Parenthetically, I’ve spoken directly with some investigators working with this or a very related agent, who have been very enthusiastic about the tolerability and the quality of the responses they’ve seen, including in some heavily pre-treated patients who are often resistant to just about everything we might offer.

3) A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2. Abstract #7506

Last year, we were privileged to have Dr. Rogerio Lilenbaum speak to us about optimizing treatment for elderly patients with lung cancer. This year, Dr. Lilenbaum will present results from an important phase III randomized study from a consortium of Brazilian oncologists (Dr. Lilenbaum hails from Brazil and continues to maintain connections to the cancer community there) that randomized patients with a marginal performance status (PS) that has historically been thought of as very marginal for standard doublet chemo (PS2 on the ECOG scale) to either carboplatin/Alimta (pemetrexed) or Alimta alone. Echoing the results from a European phase III randomized trial for elderly patients to receive either single agent chemo or carboplatin-based doublet, this trial also demonstrated a clear benefit for combination chemotherapy, with a doubling of median PFS from 3 to 6 months, and a 3.5 month improvement in median OS (5.6 vs. 9.1 months).

4) TAILOR: Phase III trial comparing erlotinib with docetaxel in the second-line treatment of NSCLC patients with wild-type (wt) EGFR. Late Breaking Abstract (LBA)#7501.

The TAILOR trial is a European study that will directly compared second-line treatment with standard IV chemotherapy to oral targeted therapy in a molecularly selected population: the 90% of patients in populations outside of Asia without an EGFR mutation (EGFR wild type). Because this is a late breaking abstract, we don’t have the results yet, but they will be clinically relevant and interesting no matter what is revealed.

5) LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Late Breaking Abstract (LBA)#7500

Though there are multiple trials already done in patients with a prospectively identified EGFR mutation who are randomized to EGFR-based therapy or standard chemotherapy, it is still very important. Based on several already completed studies with a very similar design, we can expect a significantly higher response rate and longer PFS in mutation-positive patients who received either Iressa or Tarceva. Importantly, we haven’t actually seen a significant improvement in OS with first line EGFR TKI therapy, presumably because just about all of these patients receiving first line chemotherapy cross over to EGFR inhibitor therapy next and can “make up the difference” by doing extremely well with an EGFR TKI after first line.

We actually won’t see the data until ASCO, since it’s also a late-breaking abstract, but they have the potential to be important even if many similar trials have already been reported. Why? First, afatinib is a second generation EGFR inhibitor, an irreversible inhibitor that is effective not only against EGFR but against other related receptors in the same family. It’s therefore possible that it will be significantly more effective than first generation EGFR TKIs and could perhaps lead to better results than we’ve come to expect from Iressa and Tarceva in EGFR mutation-positive patients. Second, if this trial is positive, as it should be, I would imaging that it will lead to the approval of afatinib by the FDA. If that happens, I suspect it may also be used in combination with Erbitux (cetuximab) for patients with acquired resistance to a first generation EGFR TKI, based on the preliminary but very encouraging work presented at ASCO 2011.

Finally, here’s an abstract that I’m offering as a bonus/honorable mention:

Multiplex testing for driver mutations in squamous cell carcinomas of the lung. Abstract #7505

The numbers are still small, but investigators from Memorial Sloan-Kettering will be presenting data from their pilot program of doing a battery of molecular tests on squamous NSCLC tumors in a program called “Squamous Cell Lung Cancer Mutation Analysis Project” (SQ-MAP). This work is comparable to the exciting work coming from previously described Lung Cancer Mutation Consortium, which essentially ran a battery of molecular marker tests on lung adenocarcinoma tumors. The investigators for this abstract claim that there are “actionable” targets in 60% of patients; however, the targets – FGF-1, PTEN, PIK3CA mutation, and KRAS – don’t actually have agents available to treat them today. Nevertheless, this early work is a promising step in extending the gains we’ve seen with molecular oncology in other areas of lung cancer into the understudied world of squamous NSCLC.

I’ll be providing real time updates from the ASCO meeting on Twitter. You can get those by following me on Twitter: @JackWestMD

Here’s to an exciting ASCO. More in the next few weeks.

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