Matched Targeted Therapy Extends Survival in Advanced Hard-to-Treat Cancers

Apostolia-Maria Tsimberidou, MD, PhD

Personalized therapy based on tumor molecular profiling resulted in improved overall survival (OS) for patients with advanced, hard-to-treat cancers, according to findings discussed during a press conference Saturday at the 2018 ASCO Annual Meeting.

In a retrospective analysis of data from consecutive, prospective molecularly profiled patients participating in the IMPACT trial (NCT00851032), investigators found that the 3-year OS rate was 15% for those assigned to matched targeted therapy compared with 7% for patients who did not receive precision therapy.

The median OS (9.3 vs 7.3 months; HR, 0.72; P <.001) and 10-year OS rate (6% vs 1%) also favored the matched group. The matched group also had superior progression-free survival (PFS; 4 vs 2.8 months; HR, 0.67; P <.001).

“In multivariate analysis, matched therapy was an independent factor predicting longer overall survival,” said lead author Apostolia-Maria Tsimberidou, MD, PhD, a tenured professor in the department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.

“I am optimistic that in the next few years, we will dramatically improve the outcomes for patients with cancer with increasing implementation of precision medicine,” she added.

IMPACT was designed to evaluate outcomes for patients with rare cancers or who had exhausted their treatment options. From 2007 to 2013, investigators conducted molecular testing on 3743 patients and found at least 1 molecular alteration in 1307 (35%). Tsimberidou said 1 to 50 genes were analyzed, and included genes in the PI3 kinase/AKT/mTOR, MEK/RAF, and RET pathways.

Patients were then assigned to treatment designed to block the function of the mutated or altered gene (54.4%) or unmatched treatment (45.6%). Matched treatments could include targeted therapy in combination or alone.

“Patients with tumor alterations were treated with targeted therapy when possible,” Tsimberidou said. “If matched therapy was unavailable, they received nonmatched therapy.”

Patients were aged a median of 57 years (range, 16-86), women made up 61% of the cohort, and the median number of prior therapies received was 4 (range, 0-16). Gastrointestinal tumors (24.2%) were the most common type, followed by gynecologic (19.4%), breast (13.5%), melanoma (11.9%), and lung (8.7%).

The objective response rate was 16.2% with matched therapy versus 5.4% for nonmatched. Patients in the matched group were also more likely to have stable disease lasting ≥6 months, 18.7% versus 14.7%.

Compared with other pathways, investigators found that targeting MEK/RAF and RET correlated with higher rates of stable disease lasting ≥6 months and superior survival (P <.001).

On multivariate analysis, Tsimberidou et al found that matched targeted therapy remained an independent predictor for longer OS. In contrast, molecular alterations in the PI3 kinase/AKT/mTOR pathway, age ≥60 years, poor functional status, liver metastases, elevated lactate dehydrogenase levels, decreased albumin levels, and elevated platelet counts were independently associated with shorter OS.

“PI3 kinase/AKT/mTOR pathway abnormalities were associated with inferior outcomes compared to other alterations,” Tsimberidou added.

Investigators used these factors to develop a prognostic score, with each factor representing 1 point. The median OS for patients with a score of 0 was 13.7 months (95% CI, 10.9-17.6) compared with 1.9 months (95% CI, 1.1-3.4) for patients with a score of 5 to 7.

The ongoing IMPACT2 and ASCO’s TAPUR trial are also investigating targeted therapies in this patient population. IMPACT2 compares PFS in patients who have received matched targeted therapy versus those who did not, while TAPUR assesses the efficacy of commercially-available targeted therapies in patients with advanced cancers harboring at least 1 molecular alteration.

ASCO announced in November that it would add 4 additional cohorts to TAPUR. The study now includes 16 lines of therapy and more than 500 patients.

ASCO Expert Catherine M. Diefenbach, MD, assistant professor of medicine at NYU Langone’s Perlmutter Cancer Center, said IMPACT is the first and largest study to demonstrate that matching treatment to genetic mutations in tumors improves survival for patients with advanced cancers.

“Most of these patients received drugs that were either FDA approved or were in advanced clinical trials, so people did not have to go out and reinvent the wheel to treat these patients in a completely new way,” she explained.

Diefenbach added that, prior to the advent of precision medicine, cancers were treated by speed of growth or site of origin. She noted that the genetics of a breast cancer tumor can be closer to those found in a lung cancer or a gastrointestinal cancer than another breast cancer.

“To treat a cancer based on neighborhood ignores all of these genetic differences,” she said. “Precision medicine allows us to really focus on what the genetic aberrations are in the tumor itself, not on the neighborhood of the tumor and not on the growth kinetics of the tumor. As such, this method of molecular profiling of tumors and treating on the basis of actionable mutations is the wave of the future.”

Tsimberidou AM, Hong DS, Wheler JS, et al. Precision medicine: Clinical outcomes including long-term survival according to the pathway targeted and treatment period—The IMPACT study. J Clin Oncol. 2018;36(suppl; abstr LBA2553).

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