Pancreatic cancer represents a major challenge for the drug development industry. It is the fourth leading cause of cancer death in the United States, with 37,000 people forecasted to be diagnosed every year in the US alone. In its early stages, pancreatic cancer can be treated with surgery (resection), unfortunately, however, there are still no reliable means for early detection of the disease. Consequently, only patients who are diagnosed at the disease’s early stages (20% of diagnosed patients) can actually undergo surgery, with the remaining 80% left with no real alternative. Currently, the mean life expectancy is 15-18 months for patients with early local disease and 3-6 months for patient with advanced metastatic disease. In addition to the lack of tools for early detection, pancreatic cancer cells are naturally resistant to the majority of current chemotherapies and radiation therapies. Thus there is an urgent need for new non-chemo/radio therapeutic treatments targeting both early and advanced stages.
Cell Genesys has recently published updated results from a phase II trial that evaluated GVAX as a post-resection therapy (adjuvant therapy), which aims at dealing with both local and distant tumor recurrence after surgery. As mentioned above, this kind of treatment is applicable to only 20% of diagnosed cases, who can undergo surgery, but it is still a fairly large market. Even though the overall trend in early-stage pancreatic cancer is in favor of adjuvant therapy, there are still disagreements about its feasibility. Analysis of recent trials suggests treatments based on gemcitabine (Eli Lilly‘s Gemzar®) should be favored for adjuvant therapy. Hence, GVAX for pancreatic cancer should either be proven more effective than gemcitabine or demonstrate a synergistic effect when given in combination with gemcitabine. Recent results from a clinical trial evaluating gemcitabine chemotherapy given after resection are ambivalent. Although the trial hasn’t demonstrated significant difference in overall survival (22.1 months with gemcitabine vs. 20.2 months with placebo), there was an improvement in median disease-free survival (13.4 months with gemcitabine vs. 6.9 months with the control group). The results made adjuvant therapy after pancreatic resection more acceptable, but still controversial. In earlier trials, gemcitabine in combination with chemotherapy and radiation proved to slightly improve overall survival rates when compared to chemotherapy alone (20.1-20.5 vs. 15.5-16.9 months).
Results from a phase II clinical trial evaluating GVAX for pancreatic cancer in 60 patients with early-stage pancreatic cancer were published in June this year. In 52 (88%) of the patients, the cancer had spread to regional lymph nodes by the time of the operation. GVAX was administered to patients who undergone surgery before and after standard adjuvant radiation therapy and 5-flourouracil chemotherapy. The median overall survival rate was 26.8 months for the GVAX trial, 4 months better than recently published gemcitabine results. Furthermore, median disease-free survival was approximately 16 months, which compares favorably to the 13.4 months disease-free survival recently reported in the gemcitabine study. In the GVAX trial, there were some encouraging immunological indications among patients who responded well to the treatment. These patients showed functional evidence of vaccine-induced T cell immunity against the pancreatic cancer tumor associated antigen, mesothelin. This immunological finding implies that a stimulation of the patients’ immune response against the pancreatic cancer occurred. Of note, when researchers examined general survival data for all pancreatic cancer patients resected at the medical center, who received chemo-radiation, median survival was approximately 21 months, almost 5 months shorter than in the GVAX trial. Again, in order to assess which treatment is superior, GVAX for pancreatic cancer must be compared with gemcitabine directly in a head-to-head trial. Anything else should be regarded as a vague indication, due to the differences between the trials. For example, gemcitabine was administered alone, while GVAX was part of a combination regimen. Supposedly, it gives GVAX a relative advantage, but clinical trials, which evaluated gemcitabine in combination with other treatments, could not demonstrate an additive effect. Regarding patient population, the gemcitabine trial included many more patients (179 in the gemcitabine arm), but relatively less patients whose cancer had spread to their lymph nodes (71%).
There are currently three ongoing clinical trials evaluating GVAX for the treatment of pancreatic cancer, with the majority of the related expenses is financed by the Johns Hopkins Kimmel Cancer Center. Two of these trials are a result of comparing the 3-year survival rates of the completed trial’s patients to those of general patient population who have undergone resection followed by conventional chemoradiation in Johns Hopkins. In the first 3 years following the trial, GVAX demonstrated a clear advantage over the standard therapy. However, standard therapy led to better survival rates from 3 years and beyond. This observation led researchers to the postulation that giving additional GVAX doses after the primary treatment (booster vaccination) might lead to better survival rates for longer periods. The concept of booster administration, which is common in conventional vaccines (HBV vaccine, for example) might lead to an immune response with a long-lasting effect. It might also mean that administration of GVAX should be spread over longer periods, perhaps years, in order to have an optimal long-term effect.
The first trial involves additional (booster) administrations of GVAX to patients from the completed phase II trial.
The second ongoing trial is another 60-patient trial evaluating GVAX in booster administrations following pancreatic cancer surgery and adjuvant radiation and chemotherapy.
The third trial is conducted on patients with metastatic pancreatic cancer, who, as previously stated have very poor prognosis. This population represents 80% of pancreatic patients so the market opportunity here is bigger. On the other hand, advanced pancreatic cancer is much more challenging than its early stages. With so many top selling successful cancer drugs such as Pfizer’s Camptosar® and Genentech’s Avastin® proven ineffective for treating metastatic pancreatic cancer, even after encouraging phase II results, the odds for success are rather slim. On the other hand, even a minor survival improvement may be enough, as demonstrated by Genentech’s Tarceva®, which was granted FDA approval based on a two-week survival benefit. The aggressive nature of pancreatic cancer and the absence of gemcitabine from this trial’s regimen, make it the most ambitious GVAX evaluation at the moment. The trial includes co-administration of GVAX and Imclone’s Erbitux®, a monoclonal antibody targeting EGFR, which is a member of a receptor family that leads to cell growth and proliferation. Although in recently published clinical results Erbitux failed to demonstrate anti-cancer activity in combination with gemcitabine in patients with metastatic pancreatic cancer, it might still demonstrate an additive effect in combination with GVAX. In addition, pancreatic cancer cells are notorious for their ability to inhibit anti-cancer immune response. This inhibition might be coped with (to some extent) by downregulation of members of the EGFR family, a possible effect of Erbitux. Hence, even if Erbitux cannot inhibit tumor growth in pancreatic cancer directly, it might make it more sensitive to the immune response GVAX induces in patients.
Since gemcitabine is the current standard of care in advanced pancreatic cancer, it would only be logical to try to combine it with GVAX. The overall median survival achieved by gemcitabine is in the neighborhood of 6 months, so there is a lot of room for improvement. There is also room for evaluating GVAX for pancreatic cancer in combination with other treatments. Again, combining chemotherapy agents like gemcitabine with cancer vaccines would at first seem to be counterproductive. However, clinical and pre-clinical data revealed that in some cases, gemcitabine does not suppress the host’s immune response and it might even enhance the efficacy of cancer vaccines. Another possible combination might be with anti-angiogenic agents like Pfizer’s axitinib.