ASCO followup: Patients, pathways, progress in practice

June 27, 2011 – 10:59 am 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.)

Traditionally, we have seen virtually all of the early drug development work in oncology driven by a myriad of company trials in various tumor types and, increasingly, molecular targeted therapies. Many of you will be familiar with the groundbreaking I-SPY2 (breast cancer) and BATTLE (lung cancer) studies, where the investigators attempted to use information from a patients tumor biopsy to determine what was the best therapy for each individual patient. These trials are necessarily large, time consuming and expensive to run. They are, however, the way of the future in cancer research.

At the recent American Society of Clinical Oncology (ASCO) meeting in Chicago, the outgoing president, Dr. George Sledge, announced the theme of the meeting was “Patients. Pathways. Progress,� but what does this actually mean in practice?

For me, this means the advent of molecular targeted therapy in solid tumors, where we start to find some of the driving mutations of the disease and also the adaptive resistance pathways that are beginning to be identified.

Until now, the poster children for targeted therapy with markers to indicate which patients should be treated have clearly been:

â—� trastuzumab in breast cancer (HER2-positive)

â—� imatinib in CML and ALL (Philadelphia positive BCR-ABL), GIST (KIT-positive), myeloproliferative diseases such as HES (PDGFR-positive)

â—� rituximab in NHL (CD20-positive)

â—� erlotinib in EGFR mutation positive adenocarcinomas of the lung

â—� cetuximab and panitumumab in colorectal cancer (KRAS wild type)

At this meeting, there were several promising areas where we started to see an encouraging trend in matching the therapy to the patients molecular aberration begin to emerge further.

Perhaps the most obvious example was the clear demonstration that targeting the BRAF^V600E mutation in metastatic melanoma with a specific and targeted inhibitor, vemurafenib, led to dramatic reduction in lesions and improved survival. The Phase III BRIM3 trial was a major breakthrough in melanoma because this was the first time we saw a significant advantage in favor of a molecular targeted therapy over dacarbazine (DTIC) for a period of approx. 6 to 8 months in most patients, until resistance set in and the lesions began to return.

The good news is that new combination trials are already under way looking dual inhibition of BRAF^V600E and MEK, one of the known resistance mechanisms. No doubt at the next meeting, we will see how multiple new combinations help to overcome resistance pathways being activated and improve patient outcomes in advanced melanoma even further.

Away from the plenary session, I was particularly struck by interesting data in several Phase I and II trials that may lead to some creative Phase III studies down the road. Sometimes, we learn more from several well-designed iterative early trials that teach us more about the underlying biology of the disease to more clearly define homogenous groups with clear targets than rushing hastily into a large scale registration trial and ending up with negative outcomes due to unbalanced groups and heterogeneity issues.

In some ways, these trials are best done by academia rather then individual pharma companies because they may have access to a broader array of targeted therapies than any one company can offer for treatment of a particular disease within the clinical trial setting.

One encouraging example of this new approach to clinical research was the Phase I group at MD Anderson Cancer Center, led by Dr. Razelle Kurzrock. Dr. Tsimberidou (Abstract #CRA2500 ) presented their initial attempt at matching appropriate targeted therapies to the molecular aberrations found in the tumor biopsies.

In their proof of concept study, the group hypothesized that, “Genetic and molecular analyses of patients’ cancers will identify biomarkers for targeted therapies that will improve clinical outcomes.�

To test this theory, they took tissue samples from patients undergoing Phase I clinical trials at MDACC and using the center’s CLIA laboratory, used a variety of methods such as PCR sequencing, IHC and FISH to test for known abnormalities. The targets included PIK3CA, mTOR, Raf, MEK, multikinases, KIT, EGFR, RET.

In this study, molecular analysis was ordered for 1283 patients, with adequate tissue samples being available for 1,144 of them. In all, approximately 40 percent of the patients had at least one known aberration. Interestingly, the highest number of aberrations were seen in melanoma, thyroid, colorectal, and lung cancers and the least in sarcoma and renal cell carcinomas.

The most common aberrations found in the 1,144 patients with tissue were as follows:

Source: MD Anderson Cancer Center, with permission

Matched therapy was used whenever feasible, if at least one drug in the regimen was known to inhibit the functional activity of ≥1 of the patient’s aberrations.

The results were quite interesting. Note that stable disease (SD) was defined as sustaining a stable response for at least 6 months. These were the overall results for patients with at least one aberration:

Responses	Matched Therapy (N, %)	Unmatched Therapy (N, %)
CR	4 (2)	0 (0)
PR	43 (25)	6 (5)
SD	40 (23)	12 (10)
TOTAL	47 (27)	6 (5)

Intuitively, we would expect that patients receiving an appropriate targeted therapy should do better than one without and that was what appeared to happen in these patients - the differences between the groups was significant (P<.0001), as was the overall survival, with the matched therapy group having significantly longer outcomes than the unmatched group:

Source: MD Anderson Cancer Center, with permission

In discussing the study findings Dr. Tsimberidou said, “This preliminary study strongly suggests that molecular analysis is needed to use the right drug for the right patient. Up to this point, we have treated tumor types, but this study shows we cannot treat all patients with a tumor type the same way. We need to take into consideration a number of factors, and this study suggests that a personalized approach is needed to improve clinical outcomes for patients with cancer.�

While the study concept is very promising, feasible and logical, there were a number of flaws that may have confounded the interpretation of this ambitious study.

We don’t know from the data presented, for example, how well matched the two groups were for a number of things, whether the best inhibitor in each class was used or whether they were consistently applied. No data was provided on the actual therapies received by the patients or whether the two groups were matched for each therapy evenly. Nor do we know which aberrations/tumor types had the best responders and whether the groups were evenly matched for both the aberrations and tumor types.

Clearly, if the matched group had more favorable conditions overall, then this would impact the outcomes. Unfortunately, we don’t know how well the two groups were matched from the data provided.

Dr. Kurzrock, the group leader went on to say, “This study affirms what we in the cancer community have been talking about for a decade – matching drugs to patients, the time is now. The drugs are here. The technology is here, and with our program at MD Anderson we can bring the two together in hopes to offer the most personalized care for our patients.�

Overall, I think she is right - this type of complex phase II study design is likely to be a key way forward in future. With greater rigor and attention applied to more carefully matching the groups, the concept may well help in making significant strides towards personalised medicine i.e. matching the patient’s underlying biology of their tumor to targeted therapies, as the MDACC group initially hoped to see. This process could also apply to emerging adaptive resistance pathways that will inevitably occur with different therapies in a variety of tumor types because once these are identified from the patient’s tumor tissue, appropriate treatment changes can be incorporated, potential prolonging patient outcomes even further.

References

ASCO 2011 Abstract: CRA2500 Personalized medicine in a phase I clinical trials program: The M. D. Anderson Cancer Center initiative. A.M. Tsimberidou, N. G. Iskander, D. S. Hong, J. J. Wheler, S. Fu, S. A. Piha-Paul, A. Naing, G. S. Falchook, F. Janku, R. Luthra, S. Wen, R. Kurzrock. J Clin Oncol 29: 2011 (suppl; abstr CRA2500)