Expert Details Latest Data Across GI Cancers

Susanna Ulahannan, MD

Among the gastrointestinal (GI) cancer findings presented at the 2018 ASCO Annual Meeting, the phase III PRODIGE 24/CCTG PA.6 trial results were the most significant, said Susanna Ulahannan, MD.

In PRODIGE 24, adjuvant therapy with a modified FOLFIRINOX regimen (mFOLFIRINOX) drastically improved survival compared with gemcitabine for patients with resected pancreatic cancer. mFOLFIRINOX induced a 36% reduction in the risk of death versus standard gemcitabine (HR, 0.64; 95% CI, 0.48-0.86; P = .003).¹ The median overall survival (OS) was approximately 20 months longer with the 4-drug regimen at 54.4 months versus gemcitabine at 35.0 months. Additionally, the median disease-free survival was 8.8 months longer with mFOLFIRINOX than with gemcitabine.

Also impactful were the results of the phase II PRODIGE 35/PANOPTIMOX trial, in which patients with metastatic pancreatic cancer were randomized to 3 treatment arms: arm A, FOLFIRINOX every 2 weeks for a maximum of 12 cycles; arm B, FOLFIRINOX during 4 months for 8 cycles, followed by LV5FU2 as maintenance therapy until progression; and arm C, alternating FOLFIRI.3 with gemcitabine every 2 months.

The results showed that arm B was comparable with arm A. Median OS in Arms A, B, and C were 10.1 months (95% CI, 8.5-12.2), 11.0 months (95% CI, 8.7-13.1), and 7.3 months (95% CI, 5.7-9.5), respectively. ²

“These 2 trials were very exciting,” said Ulahannan. “Seeing an OS of more than 50 months is very encouraging. We have to remember that it is a selected population and it is a toxic regimen. With all those caveats, I feel that it's very encouraging.”

Additionally, Ulahannan said that although the phase III PRODIGE 7 trial demonstrated that heated chemotherapy during resection showed no benefit in patients with advanced colorectal cancer (CRC), physicians are working to reassess which patients are most likely to benefit from therapy.³

Ulahannan also noted that incremental advances in liver cancer were seen with cabozantinib (Cabometyx), lenvatinib (Lenvima), and ramucirumab (Cyramza). Another avenue may be immunotherapy in liver cancer, she said, despite a patient’s poor liver function.

OncLive: Can you discuss the importance of the PRODIGE 24 trial?

In an interview during the 2018 OncLive^® State of the Science Summit,™ A Summer of Progress: Updates from ASCO 2018, Ulahannan, assistant professor, Section of Hematology/Oncology, associate director, Oklahoma TSET Phase I Program, Stephenson Cancer Center, The University of Oklahoma, highlighted these trials from the 2018 ASCO Annual Meeting across GI malignancies and future therapeutic approaches across the landscape.Ulahannan: The PRODIGE 24 trial in pancreatic cancer…was done in France and Canada and has changed the standard of care. The OS in pancreatic cancer, even in resectable cancer, is poor. What we have seen in trials prior in the adjuvant setting was an OS of 24 months. [We saw an OS of] 28 months in the last standard of care with gemcitabine and capecitabine.

Can you elaborate on the other PRODIGE trials that were presented?

The mFOLFIRINOX regimen that was presented at the 2018 ASCO Annual Meeting had an OS of 54.5 months, which is remarkable. We haven't seen any data like these before. From a GI perspective, that was the most exciting data from that meeting.There was also a PRODIGE study in the maintenance setting in pancreatic cancer. The initial PRODIGE study looking at FOLFIRINOX in metastatic pancreatic cancer was the first one that showed an OS of more than 11 months in the metastatic setting. That is the standard of care now. However, that's a toxic regimen. The investigators went back to see if there was something we could do to make it more tolerable for our patients.

In the maintenance setting, they did a randomized phase II trial comparing continuous FOLFIRINOX with 8 cycles of FOLFIRINOX and then 5-fluorouracil (5-FU) leucovorin as maintenance. When patients progressed, they went back and gave them FOLFIRINOX again.

What are the unanswered questions following that trial?

Outside of pancreatic cancer, what were some exciting trials presented at the 2018 ASCO Annual Meeting?

The third arm was a gemcitabine-based therapy alternating with FOLFIRI. [The randomization] showed that alternating gemcitabine with FOLFIRI was inferior. What was interesting was that the 2 other arms were comparable. This is a phase II trial, so it needs phase III data to confirm what we saw. However, now we have some randomized data showing that maintenance therapy would be an approach to pursue for these patients [who experience] a lot of toxicity.It's a selected population. [Patients] had to have to have R0/R1 resection. They had to have a performance status of 0 or 1, and they had to have CA 19-9 of less than 180, I believe. There were a lot of criteria that had to be fulfilled. However, in the trial, everything was centrally reviewed, so these are good data.There was a negative trial [that gave us data with] hyperthermic intraperitoneal chemotherapy (HIPEC). Researchers compared its use in patients with CRC with peritoneal disease only and those with liver or lung metastasis only. Patients with peritoneal disease have inferior OS compared with those with liver or lung metastasis. Even with the better treatment that we have today, the OS with peritoneal disease was about 16 months. It’s not comparable with other subsets.

HIPEC is something we have looked a lot in this group because of their poor survival. In this trial, patients received cytoreductive surgery. In the operating room, they were randomized to get HIPEC or no HIPEC. Patients had to have less than 1 mm left of disease. They also had adjuvant treatment with chemotherapy or neoadjuvant treatment. When they compared the 2 arms, there was no difference. The OS in both arms was around 41 months.

What about liver cancer?

It makes us think twice about using HIPEC. [We have to] look further [into] what subset would benefit from HIPEC. Patients had a pretty low peritoneal cancer index, so they had low-burden disease. Most of these patients had [a score] around 10, and you can get a score from 1 to 39. Figuring out the subset of patients who will benefit from HIPEC is the next challenge.In hepatocellular carcinoma, we had this void from 2007 to 2017. The only drug approved was sorafenib (Nexavar) in the setting of metastatic liver cancer. The landscape has completely changed. Today, we have sorafenib in the first-line setting and nivolumab (Opdivo) and regorafenib (Stivarga) in the second-line setting.

[We also have] data with cabozantinib and lenvatinib, as well as the new trial with ramucirumab that was presented this year. All of those [agents] are being reviewed for FDA approval. [We have] a lot of new available drugs. It’s very encouraging to see the response rates and how well our patients do on immunotherapy. In the trial [that led to the FDA approval], the median OS was 15 months.

Liver cancer is very different from other cancers because we have to look at the cancer as well as liver function and liver disease. You always have to balance these 2 things. With immunotherapy, we can treat these patients better. Immunotherapy can work even with a patient’s poor liver function. That is very encouraging and exciting.

Following the 2018 World Congress on GI Cancer, what is your perspective on the negative data with atezolizumab (Tecentriq) and cobimetinib (Cotellic) in CRC?

The other thing we see is that patients who have hepatitis B/C are eligible for immunotherapy. At the 2018 ASCO Annual Meeting, very early data on a few patients were presented with a PD-L1 inhibitor in combination with bevacizumab (Avastin). The data showed very encouraging data with about a 60% response rate. We'll see how that pans out, but it will be very interesting to see what the data will be.The challenge when we look at these mutations in different cancers [is trying] to figure out which ones are driver mutations and how to attack them when we see the same drugs reflect completely different outcomes [in different malignancies]. [This is especially true] in melanoma and CRC.

Is there anything else you want to emphasize?

It’s a danger to do all this sequencing from trials and then treat patients [by] targeting mutations. This trial shows that. We need to collect the data to know whether our patients are benefitting from it or not.In CRC, when we look at maintenance therapy, we have a lot of data for bevacizumab in combination with 5-FU. We use it all the time as maintenance to give our patients good quality of life. However, there were very little data for anti-EGFR therapy in the maintenance setting.

The phase II VALENTINO trial was a noninferiority trial looking at panitumumab (Vectibix) versus panitumumab plus 5-FU as maintenance. The study met its endpoint. Panitumumab plus 5-FU seems to be a good option as a maintenance regimen for patients with CRC who have RAS wild-type disease.

References

1. Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol. 2018;36 (suppl; abstr LBA4001). meetinglibrary.asco.org/record/159164/abstract.
2. Dahan L, Phelip JM, Malicot KL, et al. FOLFIRINOX until progression, FOLFIRINOX with maintenance treatment, or sequential treatment with gemcitabine and FOLFIRI.3 for first-line treatment of metastatic pancreatic cancer: A randomized phase II trial (PRODIGE 35-PANOPTIMOX). J Clin Oncol. 2018;36 (suppl; abstr 4000).
3. Quenet F, Elias D, Roca L, et al. A UNICANCER phase III trial of hyperthermic intra-peritoneal chemotherapy (HIPEC) for colorectal peritoneal carcinomatosis (PC): PRODIGE 7. J Clin Oncol. 2018;36 (suppl; abstr LBA3503).