Phase 2 Study of Erlotinib Combined with Adjuvant Chemoradiation and Chemotherapy in Patients with Resectable Pancreatic Cancer

Abstract & Commentary

By Samir P. Kanani, MD, Associate Clinical Professor of Neurosurgery and Radiation Oncology, George Washington University, Radiation Oncology, Inova Fairfax Hospital, Falls Church, VA. Dr. Kanani reports no financial relationships relevant to this field of study.

Synopsis: In a prospective Phase 2 study, 48 patients with resected pancreatic ductal adenocarcinoma were treated with erlotinib (100 mg daily) and capecitabine (800 mg/m2 twice daily Monday-Friday) concurrently with intensity-modulated radiation therapy followed by four cycles of adjuvant gemcitabine (1000 mg/m2 on days 1, 8, and 15 every 28 days) and erlotinib (100 mg daily). The primary endpoint was recurrence-free survival (RFS). With a median follow-up of 18 months, the median RFS was 15.6 months and the median overall survival was 24.4 months. On multivariate analysis, tumors > 3 cm predicted for a worse outcome, while the development of dermatitis predicted for an improved outcome. Grade 3/4 toxicity occurred in 54% of patients.

Source: Herman JM, et al. Phase 2 study of erlotinib combined with adjuvant chemoradiotherapy and chemotherapy in patients with resectable pancreatic cancer. Int J Radiation Biol Phys 2013;86:678-685.

This Phase 2 trial was conducted at Johns Hopkins University between March 2006 and January 2012. The 48 eligible patients all had stage I/II pancreatic ductal adenocarcinoma (PDAC) with an Eastern Cooperative Oncology Group status 0-1. The median age was 62 years. Seventy-five percent of the patients underwent a Whipple procedure while 25% underwent a distal pancreatectomy or total pancreatectomy. Patients with positive margins were eligible for protocol and comprised 17% of the patient population. More than 90% of the patients had stage II disease and 85% had lymph node involvement. The median CA19-9 was 32 U/mL. Chemoradiotherapy (CRT) was started 4-12 weeks after surgery to allow for healing. The radiotherapy dose used in this study was a standard 50.4 Gy delivered with intensity-modulated radiation therapy. Adjuvant chemotherapy consisting of erlotinib and weekly gemcitabine was given 4-8 weeks after CRT for a total of 4 months or progression. Seventeen percent had to stop CRT and 19% were unable to receive adjuvant chemotherapy. Of the patients who received adjuvant chemotherapy, 33% needed a dose reduction of either gemcitabine or erlotinib. Overall, when toxicities from the CRT and chemotherapy phases of the trial are considered collectively, 54% experienced grade 3 or higher toxicity, with anemia, neutropenia, and elevated liver enzymes being the most commonly encountered toxicities. Thirty-three percent of patients required hospital admission for a serious adverse event, including fever (8%), GI bleeding (6%), altered mental status (4%), syncope (4%), small bowel obstruction (4%), anemia (4%), abdominal pain (4%), enteritis (4%), pneumonia (4%), and intractable nausea/vomiting (2%).

The median follow-up was 18 months. The primary objective of this study was recurrence-free survival (RFS). The median RFS was 15.6 months. On multivariate analysis, size < 3 cm and development of dermatitis both predicted for an improved RFS. Median overall survival (OS) was a secondary endpoint and was 24.3 months. Local recurrences occurred 27% of the time.

Commentary

The above summarized Phase 2 study definitely adds some clinical knowledge as to the safety and efficacy of erlotinib in the management of pancreatic cancer. Erlotinib is a reversible tyrosine kinase inhibitor (TKI) that acts on the epidermal growth factor receptor (EGFR). Amplification of the EGFR gene and overexpression of the EGFR surface protein have been described in up to 60% of pancreatic tumors. In lung cancer studies, patients with wild type KRAS had improved outcomes with the use of a TKI. Wild type KRAS is only found in < 10% of PDAC specimens. The optimal approach for targeted inhibition of EGFR in pancreatic cancer, therefore, is likely to carefully select patients with wild-type KRAS and overexpression of EGFR and use erlotinib in this patient population, thus tailoring therapy to the molecular profile of the tumor.

The optimal adjuvant therapy in resected pancreatic cancer remains a very controversial topic. Practice patterns on this side of the pond differ greatly compared to our European counterparts. In the United States, the use of CRT is standard practice, as some studies have demonstrated a survival benefit.1 In Europe, adjuvant gemcitabine is the standard of care based on the results of CONKO-001,2 in which nearly 350 patients from both academic institutions and community-based hospitals were randomized to gemcitabine for 6 months adjuvant after surgical resection or observation. In patients receiving adjuvant gemcitabine, median OS was 22.1 months, similar to the study summarized above. The key difference in the two studies is that the study from Herman et al had more therapy, and thus more toxicity! Both studies had about the same rate of positive margins and positive nodes, so the baseline characteristics seem appropriately matched. I believe that immediate CRT after surgery, as was done in this trial, delays full-dose chemotherapy, thus sacrificing distant control for local control. Local control is obviously important, as a local recurrence in the pancreatic bed could be significantly morbid resulting intractable pain and other gastrointestinal issues, but this must be balanced against the risk of distant failure. The debate regarding adjuvant therapy will rage on and this study does not address this key issue. Or does it?

The rationale for this study comes from two previously reported trials. The first study, a randomized Phase 3 trial, demonstrated superior survival in patients with pancreatic cancer treated with gemcitabine and erlotinib vs gemcitabine alone in the metastatic setting.3 The second study from Bao et al is a Phase 2 study of adjuvant gemcitabine and erlotinib (without radiation) for margin-negative resected PDAC in the non-metastatic setting.4 The Bao et al trial provides a good comparison to the Herman et al trial. The Bao trial was a small 25-patient trial with similar median follow-up of 18 months, median RFS of 14 months, and 2-year OS of 53% as the above Phase 2 trial from Herman et al. The authors point out in the discussion that even though the RFS and OS were nearly identical, the local recurrence rates were lower with the addition of CRT compared to chemotherapy alone (59% vs 27%). The good news is that the local control improvement with the addition of CRT did not come at a detriment to toxicity as the Grade 3/4 toxicity was identical in the Bao et al and the Herman et al trials. What conclusions can we draw from this comparison of two Phase 2 trials? Can we conclude that the addition of radiation therapy improves local control? We have known this for decades now so this conclusion is obvious. Can we conclude that local control does not predict for OS as PDAC is a systemic disease first? This to me seems the logical conclusion taken in the context of other randomized trials such as CONKO-001. We, in the United States, need one final trial to fully understand what the Europeans have understood for almost a decade now. The current Phase 3 RTOG 0848 trial will elucidate whether the addition of erlotinib to gemcitabine confers a benefit in patients receiving chemotherapy alone. It will also clarify the benefit (or lack of benefit) of adjuvant CRT. This trial is randomizing patients to six cycles of gemcitabine alone vs six cycles of gemcitabine with erlotinib and then a second randomization between additional CRT vs observation. These results are eagerly awaited. Until then, I will continue to balance the importance of local control with distant metastasis on a case-by-case basis.

References

1. Herman JM, et al. J Clin Oncol 2008;26:3503-3510.

2. Oettle H, et al. JAMA 2007;297:267–277.

3. Moore MJ, et al. J Clin Oncol 2007;25:1960-1966.

4. Bao PQ, et al. Ann Surg Oncol 2011;18:1122-1129.