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Off-label therapies show benefit for patients with advanced, mutated cancers
CHICAGO — Patients with nine different tumor types benefited from targeted therapies administered outside of current drug indications, according to the results of a basket study presented at the ASCO Annual Meeting.
The researchers intend to expand cohorts of patients with HER-2–amplified colorectal cancer, bladder cancer and biliary cancer, as well as BRAF–mutated lung cancer, based on the observed outcomes.
John D. Hainsworth
“An increasing number of targeted agents for advanced cancer are approved now based on the presence of molecular abnormalities in the cancers,” John D. Hainsworth, MD, senior investigator at Sarah Cannon Research Institute in Nashville, Tennessee, said during a press conference. “Major successes in this area include HER-2–targeted treatment for HER-2–positive breast cancer and BRAF–targeted treatment for melanoma. We have known, though, that the same mutations are found in a wide variety of other cancers, although at a lower incidence. It is difficult to test how efficient these same treatments are, due to the difficulty of identifying the patient population.”
The MyPathway study included data from 129 patients with advanced solid tumors and no available curative therapy, whose tumors harbored the following alterations:
- HER-2 amplification (n = 53), mutation (n = 23), both (n = 5) or RBMS-NRG1 fusion (n = 1);
- BRAF V600E (n = 18) or other (n = 15);
- Hedgehog (Hh) PTCH1 (n =7) or SMO (n = 1); or
- EGFR (n = 6).
Patients enrolled in the trial had a median of three prior lines of therapy (median, 0-10).
The researchers evaluated the use of therapies targeting these alterations, including trastuzumab (Herceptin, Genentech) and pertuzumab (Perjeta, Genentech) for patients with HER-2 amplification; vemurafenib (Zelboraf, Genentech) for patients with BRAF alterations; vismodegib (Erivedge, Genentech) for patients with Hh alterations; and erlotinib (Tarceva; Genentech, Astellas) for patients with EGFR mutations.
Investigator-assessed response rate within the tumor-pathway cohort served as the study’s primary endpoint.
Eleven patients had insufficient follow-up data and were not included.
Twenty-nine patients achieved a partial response or complete response, including one complete response achieved by a patient with HER-2–amplified colorectal cancer.
Other cohorts that experienced responses included HER-2–amplified bladder cancer (n = 3) and biliary cancer (lung cancer, n = 2; salivary gland cancer, n = 1); three patients with BRAF–mutated lung cancer; one case each of BRAF–mutated ovarian cancer, cancer of unknown primary origin, colon cancer, pancreatic cancer, and head and neck cancer; and two patients with Hh alterations (squamous cell carcinoma, n = 1; cancer of unknown primary origin, n = 1).
Three patients with BRAF–mutated lung cancer have achieved objective responses, and two achieved stable disease. Based on these data, the researchers will expand this cohort.
Current response durations have continued up to 11 months. Fourteen responding patients have progressed, at a median of 6 months after treatment (range, 3-14).
The study design allows for the accrual of up to 500 patients, with expansions stopped for groups that exhibit low benefit and expanded for those who demonstrate efficacy. The researchers further intend to incorporate new agents targeted additional molecular alterations.
“I think we have shown that this trial design is feasible, with patients selected based on molecular abnormalities in their cancers rather than on their primary tumor type or primary site,” Hainsworth said. “It offers opportunities for patients with these molecular abnormalities. The MyPathway trial continues to accrue patients, and as of last week we have 200 patients accrued so far.” – by Cameron Kelsall
Reference:
Hainsworth JD, et al. Abstract LBA11511. Presented at: ASCO Annual Meeting; June 3-7, 2016; Chicago.
Disclosure: Genentech funding this study. Hainsworth reports institutional research funding from Astellas Pharma, AstraZeneca, Celgene, Genentech, Johnson & Johnson, Eli Lilly and Novartis. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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This particular trial, the MyPathway study, is both a basket trial and an umbrella trial. Basket trials look at genomic alterations across different histologies. For instance, in this study, if you have a BRAF mutation, it doesn’t matter if you have breast, lung or colon cancer — it all goes in the basket. Yet, it’s also an umbrella trial, because it includes four different baskets. We are therefore getting a lot of mileage out of this one trial.
It is much more efficient to have one trial with four different baskets than having four basket trials. For all intents and purposes, there could have been four trials, but it is significantly more time consuming to put four trials through the regulatory processes compared with one.
To me, so far, the most interesting basket here is the HER-2 basket. Patients with a variety of different tumor types — including colorectal cancers and biliary tumors — are having really nice responses, and this is going to be very important. In general, it is remarkable that we are seeing responses in diseases, like colorectal cancer, from giving a drug that would usually be given to patients with breast cancer or gastric cancer.
In the future, we will see more basket trials, because they make a lot of sense. However, organizations and institutions will need to have a system in place to be able to do them. It would be really difficult to perform a genomically based basket trial if genomic sequencing is not part of the practice, because these alterations are rare, and only very small subsets will have the alterations. For colorectal cancer, it may only be 2% or 3% that have HER-2 alterations. If you aren’t regularly checking for it, you are not going to be able to accrue patients. It is really difficult to have to put 100 patients on a trial in order to find one who is eligible, so you have to be doing sequencing regularly.
Further, a lot of academic centers that do clinical trials are very siloed. Colorectal cancer researchers do not work together with the head and neck cancer researchers — they are all in their own territories. For a trial like this, you have to have a system that allows you to work across diseases.
These barriers will not be hard to overcome, but I don’t know that all centers are ready to work with a trial like this one.
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The MyPathway study is an official research protocol that harnesses specific biologic markers present in patients to pair individual patients with selected drugs. The key here is that they are using a tumor-agnostic approach. A patient with bladder cancer may get what is traditionally thought of as a breast cancer drug, a patient with pancreatic cancer may get a lung cancer drug, and so on. This mirrors what is being done in the ASCOled TAPUR trial, in which patients with select alterations are matched to approved therapies outside of their traditional indication.
It is too early to draw conclusions, but at this point, the results are particularly encouraging for patients with colorectal, bladder and biliary tumors with HER-2 abnormalities, who are treated with pertuzumab (Perjeta, Genentech) and trastuzumab (Herceptin, Genentech). Keep in mind that this is a regimen that is only FDAapproved for breast cancer and stomach cancer at this point in time. Patients with lung cancer and BRAF mutations treated with vemurafenib (Zelboraf, Genentech), which is traditionally used in the context of melanoma, had excellent responses as well.
As the results of these studies emerge, we may shift the longstanding paradigm of treating patients based on cancer subtype and move to patients being treated based on specific molecular alterations.
Perspective
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In the era of precision medicine, the concept of a basket trial has emerged. This trial design is utilized when a given genetic alteration such as HER-2 amplification or BRAF mutations found in multiple tumor types may be amenable to the same targeted therapy. Evidence that this is true has been emerging, and the present study adds to the idea that cancer therapy can often be directed at genetic mutations rather than tumor histology. The finding that patients with lung cancer, ovarian cancer or cancer of unknown primary and BRAF mutation may respond to a BRAF inhibitor may offer some patients additional options. The same is true for HER-2 amplification in bladder cancer, biliary cancer or colorectal cancer. The type of data provided in this study from 129 patients supports the idea that off-label targeted therapy should be considered for selected patients. The demonstration of clinical benefit with off-label use of targeted agents is a positive step to support expansion of indications as well as potential reimbursement to help patients access available drugs that may be of benefit for them. In recent years, this has become a major challenge for patients who may be deprived of potentially helpful off-label therapy that is chosen based on genomic testing. The drugs are targeted to the mutations in the tumors, and this provides a compelling rationale for the therapy. The demonstration of clinical benefit provides an important advance and a step in the right direction to increase options for patients.
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