Preparing for pancreatic cancer ‘tsunami’ ahead

Locally advanced disease

For locally advanced disease, studies have failed to show a benefit of adding radiation after chemotherapy, but radiation oncologists who argue that, “when your therapy gets better, my therapy gets better,” have a valid point, Dr. Tempero said.

For that reason, the Radiation Therapy Oncology group launched a trial to look at gemcitabine/nab-P with and without radiation, but had difficulty with enrollment due to resistance among some physicians who are opposed to radiation in this setting .

“So I don’t know that we will ever answer this question in locally advanced disease. What I can say ... is, in my mind, in locally advanced disease, the most important component is the chemotherapy,” she said.

Metastatic disease

When it comes to trials involving pancreatic cancer patients with metastatic disease, it is important to understand – and to convey to policymakers – that the goal is not only to provide better care in these patients who are at the end of their life, but also to identify strategies that can be used in the adjuvant and neoadjuvant settings, as this is part of the “overall mission of helping patients to feel better and live longer and be cured,” Dr. Tempero said.

One regimen currently used in the metastatic setting is FOLFIRINOX, which was shown in the Prodige 4-ACCORD 11 trial to be superior to gemcitabine monotherapy for survival (hazard ratio, 0.57).

“This is the first time we ever saw a hazard ratio below 0.6 in this disease,” she said, adding that for some patients this means “they can get tremendous benefit, they can come off chemotherapy and have a chemotherapy holiday,” she said.

That said, it’s a tough regimen, she added, explaining that it has dominating toxicities of myelosuppression, diarrhea, and neuropathy that can be irreversible.

Frail patients may not be able to tolerate the regimen, but modifications to the regimen may help. For example, the 5-fluorourasil bolus is often omitted, and doses are sometimes reduced. Chemotherapy holidays can also be of benefit.

Another regimen for the metastatic setting involves the use of nab-P plus gemcitabine, which was shown in a phase III trial to improve survival (HR for death, 0.72).

The results aren’t quite as dramatic as those seen with FOLFIRINOX, but the regimen is slightly easier to manage, Dr. Tempero said, adding: “It’s still not a walk in the park.”

Myelosuppression, arthralgias, and neuropathy still occur, she explained.

Gemcitabine/capecitabine, which has been shown to improve progression-free survival, can also be used, and may be preferable in elderly patients who aren’t fit enough for the other regimens, she said.

“When I select treatment, I really sit down with the patient, and I look at their comorbidities and let them review the toxicities. They decide,” she said, explaining that she provides recommendations based on their concerns and input. “We do have a conversation and we talk about the goals of treatment, we talk about the toxicities.”

Future efforts for metastatic disease should build upon both FOLFIRINOX and gemcitabine/nab-P, she said.

However, because of the difficulty with administering FOLFIRINOX, only two of the 54 open phase I-III trials ongoing in the United States for metastatic disease incorporate the regimen.

Other treatment options include gemcitabine/cisplatin, GTX (gemcitabine/docetaxel/capecitabine), and gemcitabine/erlotinib. The former remains in the NCCN guidelines, primarily for those with hereditary forms of pancreatic cancer, and in particular for those in the DNA repair pathway (BRCA patients, for example).

“We actually have trials now focusing on just BRCA-related pancreatic cancer,” she said, noting that these patients are “exquisitely sensitive to cisplatin and don’t need a harsh regimen like FOLFIRINOX to get the same benefit.

GTX is a very active regimen, although it has never been compared with gemcitabine monotherapy in a randomized trial. However, because of its clear activity it remains in the NCCN guidelines as an option.

Gemcitabine/erlotinib also remains in the guidelines because of a tiny trial that showed a small benefit, but it is not a preferred combination, she said.

Future therapies

Efforts going forward are focusing on finding drugs that inactivate activated RAS, which is “a really big driver” in many cancers, as well as on addressing the microenvironment (such as the desmoplastic stroma that may help encourage invasion of metastases and/or impede drug delivery to the cancer), Dr. Tempero said.

“So there is a lot of interest right now in various forms of immunotherapy or in stromal remodeling so we can see what impact that has on the progression of this disease,” she said, noting that new agents in registration trials include ibrutinib, laparib, PEGPH20, and insulinlike growth factor 1 (IGF-1) inhibitors, and those in planning stages include chemokine (C-C motif) receptor 2 (CCR2) inhibitors and palbociclib.

“And I think we have opportunities in the maintenance setting and in the neoadjuvant setting to do window-of-opportunity trials where we can test new concepts, where we can get pharmacodynamic and biologic data to understand what these new agents are doing,” she said.