Molecular targeted therapy progress with lung cancer

July 5, 2011 – 1:06 pm by Chris

(This is a guest post from Sally Church, Ph.D, who writes the Pharma Strategy Blog. If you are on Twitter, follow her here.)

In this second part of the ASCO report, we look at another area where significant strides are being made with molecular targeted therapy, lung cancer. For years, this disease has seen small incremental improvements in outcomes with single, double and even triple combination therapies with chemotherapy. More recently, we have seen new progress in various clinical trials, at least in adenocarcarcinomas, and new targets are being identified in both squamous and non-squamous lung cancers, which may form new targets for companies down the line.

Continuing with this year’s congress theme of “Patients. Pathways. Progress� at ASCO, one impressive and well-organized study that caught my attention amongst the thousands of abstracts was CRA7506, “Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC).� The presentation was given by Dr Mark Kris from Memorial Sloan Kettering Cancer Centre (MSKCC).

In the last five years we have seen new molecular targeted therapies emerge in the treatment of adenocarcinoma of the lung for patients with wild-type EGFR mutations (erlotinib) and ELM4-ALK translocations (crizotinib), demonstrating that identifying and targeting a driver mutation can lead to better patient outcomes. There are many more in development targeting molecular aberrations, including MET amplications (ARQ-197 and METMab). The question the researchers asked in this important study was could other driver mutations be identified in adenocarcinomas to help match treatment to the underlying aberration?

Accordingly, the 14 member LCMC group was created with the ambition, “to determine 10 driver mutations in tumors from 1,000 patients and to give the results to clinicians for care and entry onto targeted therapeutic trials based on these findings.�

The group collected and tested tissue samples from patients (n=831) using CLIA labs from patients with lung adenocarcinoma for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS. In addition, standard multiplexed assays and FISH were used for ALK rearrangements and MET amplifications.

The analysis of the data revealed some interesting findings.

At the time of the analysis, according to the researchers, a “driver mutation� was detected in 60 percent of tumors analyzed. The key aberrations (not all of the 10 identified were mutations, some were translocations and other ampliflications) were detected as follows:

Aberration	Number	Percentage
KRAS	107	25%
EGFR	98	23%
ALK translocation	14	6%
BRAF	12	3%
PIK3CA	11	3%
MET amplification	4	2%
HER2	3	1%
MEK1	2	0.4%
NRAS	1	0.2%
AKT1	0	0%

Source: Kris et al., (2011)

What particularly struck me was that Dr Kris observed that 95 percent of molecular lesions tested above were mutually exclusive.

Clearly, uncovering a positive EGFR mutation test was an indication for the physician to treat the patient with an approved EGFR inhibitor such as erlotinib, as indicated by ASCO and NCCN Guidelines, to ensure the best chance of success and prolonged outcome for the patient.

No other molecular targeted therapies are as yet indicated for the other aberrations identified in the study. Patients with those aberrations were therefore offered the opportunity to participate in LCMC-linked trials of agents targeting the aberration identified, such as crizotinib with EML4-ALK translocations. Given that Pfizer, the manufacturers, have filed with the FDA for approval of this agent, we may well have a new approved treatment in this subset of adenocarcinoma patients very soon.

The importance of offering clinical trials to determine if treatment with an appropriate molecular targeted therapy cannot be understated. While they may offer the best chance of success, there is no guarantee that they will actually work. For example, we know that BRAF^V600E mutated metastatic melanomas are exquisitely sensitive to treatment with a specifically targeted inhibitor such as vemurafenib, but the same drug is not effective in BRAF^V600E mutated colon cancers. In lung adenocarcinomas? We don’t know yet.

The question then is why does this happen?

Well, one conclusion might be that the aberration could be a passenger rather than a driver or simply overexpressed rather than functioning as a critical aberration. For this reason, I would urge caution regarding the researchers claim that they have identified ten ‘driver’ mutations until clinical data from randomised patient trials is available to substantiate this theory since some may well turn out to be mere passengers.

Overall, the identification of potential molecular targets in lung adenocarcinomas for clinical trial verification is a very useful finding from this study, as well as serving as a feeder mechanism that may well have speeded up clinical trial enrollment in several relevant ongoing studies with specific patient criteria regarding these abnormalities.

The other side of the coin is that not all targeted therapies are equal, even within the same category. For example, erlotinib, a small molecule tyrosine kinase inhibitor (TKI) has been the only EGFR inhibitor to show to improved survival in patients with adenocarcinoma of the lung expressing EGFR mutations. The data with monoclonal antibody inhibitors to EGFR, such as cetuximab and panitumumab, has been largely negative in lung cancer. These two therapies have, however, been shown to improve survival in colorectal cancer (CRC) with wild type KRAS mutations, whereas erlotinib was ineffective in CRC, a most perplexing scientific conundrum indeed!

Thus, while we know that EGFR inhibitors are the most useful therapeutic strategy for patients with EGFR mutations at present, approximately 50% of those patients will unfortunately develop resistance due to new mutations developing such as T790M, which occurs in approximately 50% of the cases.

The question here, therefore, is what strategies could be employed to overcome the acquired resistance to erlotinib?

Recently, several trials reported mixed data with various EGFR inhibitors. At ESMO last September, for example, initial results were presented by Dr Vincent Miller on afatinib in the LUX-LUNG1 trial, showing encouraging activity in terms of response rates, but no benefit in overall survival when afatinib was combined with erlotinib over erlotinib alone. Since then, a small trial published data for the combination of erlotinib with cetuximab after initial erlotinib therapy and reported no responses in the 19 patients evaluated.

Sometimes, however, the most interesting and unexpected data at a meeting can be found in a poster session!

At ASCO, Dr. Janjigian and colleagues reported phase Ib data in patients with lung adenocarcinoma (n=45) who had developed acquired resistance to erlotinib and were treated with the combination of afatinib plus cetuximab. Some had developed the expected T790M mutation, others had not. Based on these two studies cited above, I would not have expected much from combining afatinib with cetuximab in patients who had received prior erlotinib therapy.

However, the waterfall plots clearly indicated that even though this was only a Phase I study, something really very interesting was going on in their patients:

Source: Janjigian et al., (2011)

Accordingly, the authors stated simply, “Efforts are ongoing to elucidate the mechanisms underlying the observed tumor regressions and possible mechanisms of progression on the combination.”

While these results will need to be validated in larger scale randomised trials, the data they collected in erlotinib refractory patients treated with afatinib and cetuximab were stunning and worthy of further investigation.

In conclusion, after years of treating all lung cancer patients similarly with chemotherapy, we can see at this ASCO meeting that, at least in adenocarcinomas, we are now beginning to make substantial progress not only in delineating the driving mutations, but also mechanisms of acquired resistance to erlotinib and potential new molecular targeted therapies for both ends of the spectrum - that’s good news for patients and oncologists alike.

References:

ASCO 2011 Abstract CRA7506:

M. G. Kris, B. E. Johnson, D. J. Kwiatkowski, A. J. Iafrate, I. I. Wistuba, S. L. Aronson, J. A. Engelman, Y. Shyr, F. R. Khuri, C. M. Rudin, E. B. Garon, W. Pao, J. H. Schiller, E. B. Haura, K. Shirai, G. Giaccone, L. D. Berry, K. Kugler, J. D. Minna, P. A. Bunn Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: The NCI’s Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 29: 2011 (suppl; abstr CRA7506)

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=81670

Janjigian YY, Azzoli CG, Krug LM, Pereira LK, Rizvi NA, Pietanza MC, Kris MG, Ginsberg MS, Pao W, Miller VA, Riely GJ. (2011) Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. Clin Cancer Res. 2011 Apr 15;17(8):2521-7. Epub 2011 Jan 19.

http://www.ncbi.nlm.nih.gov/pubmed/21248303

ASCO 2011 Abstract 7525:

Y. Y. Janjigian, H. J. Groen, L. Horn, E. F. Smit, Y. Fu, F. Wang, M. Shahidi, L. J. Denis, W. Pao, V. A. Miller Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 29: 2011 (suppl; abstr 7525^)

http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78057

Tags: adenocarcinoma, ASCO. lung cancer, erlotinib, molecular therapy