Genomic Testing Makes Inroads After First-Line Therapy in Metastatic Pancreatic Cancer

For metastatic pancreatic cancer, treatment options expanded in late 2018 through 2019 with FDA approvals of larotrectinib (Vitrakvi) for the treatment of solid tumors with NTRK fusions; entrectinib (Rozlytrek), another pan-tumor agent for NTRK fusions; and olaparib (Lynparza), a PARP inhibitor that can be used as maintenance treatment for some patients with BRCA mutations.¹ The recently updated American Society of Clinical Oncology (ASCO) guidelines for the treatment of metastatic pancreatic cancer offer guidance on how to incorporate these therapies into clinical practice.

Notably, the 2020 update recommends early testing for genomic alterations.¹ “Pancreas cancer has lagged, compared [with] other solid tumor types, in molecular testing and transitioning from indiscriminate chemotherapy to genome immune targeted drugs,” said Gregory Botta, MD, PhD, a medical oncologist at Moores Cancer Center at UC San Diego Health in La Jolla, California. “These guidelines push oncologists across the board to start implementing next-generation sequencing into their practice, and that can change outcomes for our patients.”

Median overall survival (OS) for patients with advanced metastatic disease is about 12 months,² and fewer than 10% of patients are alive 5 years after their initial diagnosis.³ Although targeted therapies have offered hope to patients with many other types of cancer, including lung cancer and breast cancer, there were few good treatment options for patients with metastatic pancreatic cancer until recently.

Early Germline and Somatic Testing Recommended

The ASCO guidelines recommend “early testing for actionable genomic alterations…for patients who are likely to be potential candidates for additional treatment after first-line therapy.”¹ Germline and tumor (somatic) testing are recommended, and testing should look for microsatellite instability/mismatch repair deficiency, BRCA mutations, and NTRK fusions.¹ Ideally, genomic testing should be conducted as part of an initial assessment so results are available in a timely fashion when clinical decisions are made.

Integrating genomic testing into clinical practice will require new systems. “There’s a whole pipeline that needs to be developed for each individual practice and clinician,” Botta said. A discussion with the patient focusing on the pros, cons, and logistics of genomic testing is recommended; the updated ASCO guidelines specifically state that this conversation should include “the frequency of actionable findings, treatment implications of testing results, and genetic counseling related to germline testing.”

Deciding which tests to order is important, as a variety of institutions and companies now offer next-generation sequencing. Oncology practices must set aside time to complete required paperwork and develop a process to ensure timely review of test results.

Targetable Genomic Alternations Affect a Minority of Patients With Pancreatic Cancer

Although the updated ASCO guidelines are a significant step forward, they “will have a modest impact on the overall care of patients with pancreatic cancer,” said Minsig Choi, MD, director of outpatient medical oncology and gastrointestinal medical oncology at Stony Brook Cancer Center in New York.

“Targeted therapies are helpful for patients with these alterations, but most patients with advanced pancreatic cancer are still left with conventional chemotherapy,” Choi said.

However, early genomic testing gets targeted therapies to patients who are likely to benefit from them, and research suggests that targeted therapy may improve clinical outcomes. According to a retrospective analysis of the Know Your Tumor registry trial, patients with pancreatic cancer who had actionable molecular alterations and received a matched therapy had a significantly longer median overall survival than patients who only received unmatched therapies (2.58 years vs 1.51 years). The overall survival for patients who received a matched therapy was also significantly longer than the OS rate for patients who did not have an actionable molecular alteration (2.58 years vs 1.32 years).²

Larotrectinib or Entrectinib Recommended for Patients With NTRK Fusions

For the first time, treatment with larotrectinib or entrectinib is recommended in the second- and later line settings for patients with tumors harboring NTRK fusions. Both drugs were approved by the FDA for patients with solid tumors on the basis of basket trials that included few patients with pancreas cancer.

The safety and efficacy of larotrectinib was established in a study of 3 trials involving 55 patients with TRK fusion-positive tumors; 1 of those patients had pancreatic cancer. The overall rate of response was 75%; 13% of patients experienced a complete response, and 62% (including the 1 patient with pancreatic cancer) experienced a partial response. Seventy-three percent of patients were progression free at 6 months; 55% were progression free at 1 year.⁴

Entrectinib was tested in more than 50 patients with solid tumors with NTRK molecular alternations. The objective response rate was 57.4%, with 4 complete responses. A partial response was observed in 2 of the 3 patients with pancreatic cancer. Median progression-free survival (PFS) was 11.2 months and OS was 20.9 months.⁵

“These were not randomized trials and only included small numbers of [patients with pancreatic cancer], but the response rates were so overwhelmingly high compared [with] standard treatment that these drugs were included in the guidelines,” Botta said. “Currently, overall survival with chemotherapy in a second-line setting is about 6 months; with best supportive care, it’s about 2.8 months. When a study shows overall survival of 21 months, as with entrectinib, that’s huge.”

To date, larotrectinib and entrectinib have not been studied head-to-head, so “the best choice remains unknown,” said Ryan W. Huey, MD, assistant professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. Future research may provide additional guidance.

At this point, Botta said, there’s “a bit more data” to support entrectinib. “Entrectinib improved both PFS as well as OS; larotrectinib improved PFS but not OS,” he said.

A Second-Line Option for Patients With BRCA Mutations

Patients who have a germline BRCA1 or BRCA2 mutation and have completed at least 16 weeks of first-line platinum-based chemotherapy without disease progression may either continue chemotherapy or switch over to olaparib maintenance, according to the guidelines.1 The recommendation to consider olaparib is based on the phase 3 POLO trial (NCT02184195), in which some patients were started on maintenance olaparib 4 to 8 weeks after chemotherapy.³ Their outcomes were compared with those of patients who received a placebo after completing chemotherapy. Median PFS was significantly longer in the olaparib group than the placebo group (7.4 months vs 3.8 months). However, an interim analysis of OS did not show a significant difference (18.9 months with olaparib vs 18.1 with placebo).³

Of note, this trial compared olaparib to a treatment holiday, which is not the current standard of care, said Alok Khorana, MD, director of the Gastrointestinal Malignancies Program at the Cleveland Clinic in Ohio and a contributor to the updated ASCO guidelines. “A more appropriate control would have been continued chemotherapy,” he said.

Additional studies may provide further information and eventually help clinicians appropriately sequence treatment for patients with BRCA mutations. At present, though, olaparib may be a good option for those who have plateaued on chemotherapy. “You can say, ‘We’ve exhausted the efficacy of chemotherapy. Let’s change you over to olaparib, so instead of coming into the infusion center 2 or 3 times a month, you can take olaparib on your own at home,’” Botta said.

Olaparib may also be a good option for patients who are experiencing chemotherapy-related toxicities, he said. Switching these patients to olaparib may allow them to regain quality of life.

Addressing Cost and Logistical Challenges

Scientifically, the guidelines are clear: there is significant potential benefit to genomic testing for all patients with pancreatic cancer. However, deciding to test or not is a complex decision that must be made in concert with the patient.

Cost is a major concern for many patients. “Next-generation sequencing is now widely available, and costs have dropped significantly,” Khorana said. “Some tests are covered by insurance, and some patient advocacy organizations are also arranging for expense-free testing for patients.” However, in light of uncertainty regarding insurance coverage and copayments, patients may be hesitant to agree to genomic testing. Of 1856 patients initially referred to the Know Your Tumor registry, a program of the Pancreatic Cancer Action Network that coordinates molecular testing and delivers a report of molecularly tailored treatment recommendations, 15 patients declined to move forward with the program because of the perceived risk of financial burden, even though “most patients had adequate insurance or were deemed to be eligible for financial assistance through the laboratories, and patients were reassured that [the] clinical coordination team would help to negotiate to minimize the cost of molecular testing.”²

When cost is a consideration and the likelihood of discovering an actionable alteration is low, patients may decline genomic testing despite potential benefits. A frank discussion of costs and treatment alternatives is necessary, and physicians must allow time to effectively hear and address patient concerns. “It’s best to ensure patients are fully informed so there are no ‘surprise billing’ issues,” Khorana said.

Genomic testing may enable patients to enroll in targeted clinical trials. “Identification of alterations may help direct patients to specific mutation-directed trials and thereby improve access to newer drugs,” Khorana said. Already, clinical trials are studying various KRAS mutations and the response of patients with these mutations to specific therapies. In the future, scientists may identify additional actionable alternations, allowing clinicians to target various subsets of pancreatic cancer more precisely.

“All pancreas cancers derive in the pancreas, but everybody’s pancreas cancer is different,” Botta said. “Genome sequencing allows us to personalize treatment, so we get the appropriate therapy with the appropriate drugs to the right patients.”

_References:

_{1. Sohal DPS, Kennedy EB, Cinar P, et al. Metastatic pancreatic cancer: ASCO guideline update. J Clin Oncol. 2020;38(27):3217-3230. doi:10.1200/JCO.20.01364}

_{2. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020;21(4):508-518. doi:10.1016/S1470-2045(20)30074-7}

_{3. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. doi:10.1056/NEJMoa1903387}

_{4. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448}

_{5. Doebele R, Paz-Ares L, Farago AF, et al. Entrectinib in NTRK-fusion positive (NTRK-FP) non-small cell lung cancer (NSCLC): Integrated analysis of patients enrolled in three trials (STARTRK-2, STARTRK-1 and ALKA-372-001). Presented at: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. doi:10.1158/1538-7445.AM2019-CT131}