By Emily Benesh, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health
It is an exciting time for patients and their doctors fighting advanced hepatocellular carcinoma (HCC). In mid-2016 the HCC community witnessed the first randomized trial to successfully improve survival outcomes in Nexavar® (sorafenib, Onyx/Amgen/Bayer)-pretreated HCC when the multikinase inhibitor Stivarga® (regorafenib, Bayer) demonstrated a 38% reduction in the risk of death compared with placebo in the Phase III RESOURCE trial.1 This led to submission of a supplemental new drug application with the U.S. Food and Drug Administration (FDA) in November 2016. Additionally, Opdivo® (nivolumab, BMS/Ono Pharmaceuticals) is showing very promising activity as treatment of advanced HCC, and the excitement around these results was palpable at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in San Francisco.
Historically, the unmet needs in HCC have been insurmountable. Even with the best therapeutic options available, the prognosis for advanced HCC has been quite poor; first-line patients receiving the standard of care, Nexavar, have a median overall survival of 10.7 months. In 2007, Nexavar, a multityrosine kinase inhibitor, was established as the first targeted agent FDA-approved in this indication. It achieved this by besting a placebo control with a 2.8-month improvement in overall survival,2 although patients did not experience improvements in time to symptomatic progression or complete responses with use of this agent. Additionally, use of Nexavar came at a high price. In the SHARP trial, 80% of Nexavar-recipient patients experienced serious adverse events including diarrhea, hand-foot skin reaction and others.2
The last nine years have seen novel therapeutic contenders struggle to improve outcomes and unseat Nexavar as front-line therapy. This is due, in part, to liver dysfunction (cirrhosis) present in many HCC patients as well as other comorbidities resulting from infection with hepatitis B or hepatitis C, and/or occurrence of non-alcoholic fatty liver disease. In practice, systemic therapies such as Nexavar are limited to patients with the least degree of cirrhosis (Child-Pugh A). Those with greatly impaired liver function (Child-Pugh C) are often unable to tolerate current therapeutic options and generally receive only best supportive care. Even those with reasonable liver function may struggle to tolerate combination therapies that include Nexavar as a backbone.
Thus, a novel agent is greatly needed that makes strides in both efficacy and tolerability in order to encompass more patients in the treatable population. Such an agent would find an open market with a reasonable patient base; in 2016 HCC ranked as the 14th most commonly diagnosed cancer in the United States with an incidence of roughly 30,000 newly diagnosed patients.3 In Eastern countries the population suffering from HCC is slightly larger; it ranked ninth in Japan with nearly 36,000 new cases reported in 2016.3
Against this backdrop of high unmet need and reasonable opportunity, BMS/Ono entered the competitive landscape in 2012. Opdivo is a human immunoglobulin IgG4 monoclonal antibody that binds to the programmed cell death protein-1 (PD-1) receptor on immune cells, releasing tumor-driven inhibition of immune reactions. Results of Opdivo trials have shown incredible promise with overall survival gains and remarkably durable responses in multiple tumors, leading to its FDA approval in metastatic melanoma (alone or in combination with Yervoy® (ipilimumab, BMS/Ono)), metastatic non-small cell lung cancer, advanced renal cell carcinoma, classical Hodgkin’s lymphoma and squamous cell carcinoma of the head and neck.
The CheckMate-040 Phase I/II trial (NCT01658878) was initiated to evaluate the safety, tolerability, dose-limiting toxicities and maximum tolerated dose of Opdivo in 1) uninfected HCC subjects, 2) HCC patients with hepatitis B, and 3) HCC patients with hepatitis C. Patients had unresectable advanced HCC, with a Child Pugh score of ≤7 (dose escalation) or ≤6 (dose expansion). Patients could not have active HBV or HCV and were required to be on antiviral therapy with a viral load of <100 IU/mL. Subpopulations of patients were Nexavar-naïve and Nexavar-refractory.
The patient characteristics between the dose escalation and expansion cohorts were well balanced; both cohorts favored male subjects (75% and 80%, respectively) and were enriched for Asians (38% and 47%, respectively). Seventy-six percent of patients were systemic therapy-experienced, two-thirds of whom had received prior Nexavar. In October 2016, interim data were presented for 48 patients treated in the dose escalation cohort and 214 patients in the dose-expansion cohort,4 and Friday at the ASCO Gastrointestinal Cancers Symposium in San Francisco updated results were presented.5 As of the data cut-off (August 8, 2016), investigators had treated 262 patients across the dose escalation and expansion phases of the trial. Twenty-five percent of patients experienced Grade 3/4 or greater adverse events, including AST increase (10%), ALT increase (6%) and lipase increase (13%). While hematologic liver parameters are of particular concern to the HCC patient population, these were considered manageable and did not result in hepatitis. Health-related quality of life outcomes, as measured by EQ-5D index scores, did not show differences in first- or second-line patients and were stable from baseline to week 25. Thus, the relatively mild toxicity profile of Opdivo monotherapy in these pretreated HCC patients was encouraging.
In second-line Nexavar-experienced patients, 37 patients were evaluable in the escalation cohort and 145 were evaluable in the expansion cohort. Investigator assessed objective response rate (ORR) were 16.2% and 18.6% in the escalation and expansion phases, respectively, including complete response (CR) rates of 8.1% and 2.1%. Blinded independent central review noted lower rates of CR (2.7% and 0.7%, respectively), but the ORR was only slightly lower than that reported by investigators (18.9% and 14.5, respectively). The duration of response was 17.1 months in the dose escalation cohort and had not been reached in the dose expansion cohort. The median overall survival of the dose escalation cohort was 15.0 months; it was 13.2 months in the dose expansion cohort. At nine months’ follow-up, 67% and 71% of patients were alive in the escalation and expansion cohorts, respectively. In the escalation cohort, 46% of patients were alive at 18 months. In the dose expansion Nexavar-naïve cohort (69 patients), 21.7% had an objective response (all partial). Six- and nine-month overall survival rates were 87% and 77%, respectively. Expression of PD-L1 did not correlate with response to Opdivo in either patient population. Despite PD-L1 level appearing inconsequential to outcomes in this population, the discussant stated that detailed biomarker analyses (e.g., mutational burden, tumor-infiltrating lymphocytes or immune gene signatures) would further enrich the population for responders and improve survival rates even more.6
Results from the CheckMate-040 trial were very promising. Cross-trial comparisons of Opdivo and Nexavar suggest that Opdivo far outstrips efficacy numbers put up by Nexavar in previous trials (in the SHARP trial, ORR was 2% and median overall survival was 10.7 months2). Based on these encouraging results, BMS is pursuing several avenues to establish and expand the reach of Opdivo in this space. In November 2015, BMS initiated a randomized global Phase III head-to-head trial (CheckMate-459) of Opdivo versus Nexavar. The trial is recruiting treatment-naïve, Child-Pugh A advanced HCC patients in the United States, EU, Asia and Australia. According to the presenter, patient recruitment for CheckMate-459 is almost finished. In addition, BMS is exploring Opdivo use as a monotherapy and in combination with Yervoy or other novel agents in Phase I and II trials in various HCC treatment settings.
While the BMS/Ono developmental program has a head start, they are not alone in pursuing opportunities in the HCC space. Merck also has a strong program for Keytruda® (pembrolizumab, Merck & Co.). An ongoing Phase III trial (Keynote-240, NCT02702401) is investigating Keytruda versus best supportive care in relapsed/refractory HCC. An ongoing randomized Phase II trial is pitting the PD-1 inhibitor durvalumab (AstraZeneca) monotherapy versus the CTLA4 inhibitor tremelimumab (AstraZeneca) monotherapy versus the durvalumab/tremelimumab combination in Nexavar-refractory patients (NCT02519348). Another agent in development is Pexa-Vec® (pexastimogene devacirepvec, SillaJen), an oncolytic virus that also delivers GM-CSF to tumor cells. Pexa-Vec is being paired with Nexavar versus Nexavar monotherapy as first-line therapy in Child-Pugh A advanced HCC in a Phase III trial (NCT02562755). Beyond immunotherapy approaches, other targeted therapy agents are in late-stage development in HCC: Stivarga has been filed for FDA approval in second-line HCC based on the positive RESOURCE trial results, and Phase III trials are ongoing for Cabometyx® (cabozantinib, Exelixis/Ipsen), Cyramza® (ramucirumab, Eli Lilly), and tivantinib (ArQule) in second-line, and Lenvima® (lenvatinib, Eisai) in first-line.
Thus, a host of agents are seeking entry into a space that promises to become increasingly crowded in the near future. It remains to be seen whether final results from the dose expansion cohort of CheckMate-040 might prompt an accelerated approval approach, or whether BMS will wait to file until CheckMate-459 data report. Nonetheless, the data that are unfolding continue to support a potential future scenario in which Opdivo emerges triumphant as a new leader in HCC management, potentially unseating Nexavar in the front-line and bringing a more effective and tolerable treatment to a very ill patient population greatly in need of some hope.
By Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Before Cyramza® (ramucirumab, Eli Lilly and Co) was approved by the U.S. Food and Drug Administration (FDA) in 2014, no targeted therapy regimens were approved for use in relapsed/refractory gastric cancer. Cyramza’s approval as a monotherapy or in combination with paclitaxel after prior fluoropyrimidine- or platinum-containing systemic therapy was based on the positive results of two Phase III studies in relapsed gastric patients: the REGARD trial, which showed a significant overall survival (OS) benefit of 5.2 months for Cyramza versus 3.8 months for placebo,1 and the RAINBOW trial, which compared Cyramza plus paclitaxel versus paclitaxel alone, demonstrating a significant progression free survival (PFS) and OS benefit for the Cyramza combination (OS: 9.63 months in Cyramza plus paclitaxel arm versus 7.36 months in paclitaxel alone arm).2 Cyramza had a significant first-to-market advantage in this indication and is currently highly utilized in this space (30.4% as monotherapy or with paclitaxel in second-line in the U.S.).3 However, given the limited number of treatment options, new agents still have a lot of potential, including immunotherapies, which have already made a splash in other solid tumor types.
While gastric cancer is a relatively rare tumor type in the United States (ranks 16th in terms of incidence), it is the most commonly diagnosed tumor type in Japan.3 In part due to this, Ono Pharmaceuticals took the lead in evaluating immunotherapy in gastric cancer in Asia Pacific. In 2014, Ono Pharmaceuticals (which is co-developing Opdivo along with Bristol-Myers Squibb) initiated a randomized (2:1), double-blind, Phase III trial of Opdivo® (nivolumab) in gastric and gastroesophageal junction (GEJ) cancer patients in Japan, Korea and Taiwan (ONO-4538-12; NCT02267343). In this trial, Opdivo (3 mg/kg q2w) was compared against placebo in patients refractory or intolerant to standard therapies. The primary endpoint was OS. In yesterday’s oral abstract session at the 2017 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, positive data from this trial were presented.4 The trial enrolled 493 patients with unresectable advanced or recurrent gastric/GEJ cancer who had failed two or more previous chemotherapy regimens, including Cyramza. As of the data cut-off on August 13, 2016, 5.6 months after the last patient was randomized, median OS was 5.32 months with Opdivo versus 4.14 months with placebo (hazard ratio, 0.63; 95% confidence interval (CI), 0.50-0.78; p<0.0001), and OS rates at six and 12 months were 46.4% versus 34.7% and 26.6% versus 10.9%, respectively. The overall response rate was 11.2% with Opdivo versus 0% with placebo (p<0.0001). Median PFS was 1.61 months with Opdivo versus 1.45 months with placebo (HR, 0.60; 95% CI, 0.49-0.75; p<0.0001). Grade ≥ 3 drug-related adverse events (AEs) occurred in 11.5% of Opdivo-treated patients and in 5.5% of placebo-treated patients; 2.7% and 2.5% of patients, in the respective arms, discontinued study treatment due to drug-related AEs (any grade). The most common AEs were pruritus, diarrhea, rash, fatigue, and decreased appetite. These data were well received by the conference audience. Of particular excitement was the characteristic OS plateau or “tail” in the Kaplan-Meier curve that we have come to expect from the checkpoint inhibitor class of immunotherapy agents; while the OS difference at the median was modest (1.18 months), a strong separation between the two curves that appears to be maintained long-term. Biomarker analysis was not reported, but is ongoing.
Not surprisingly, Ono has already filed for approval of Opdivo in gastric cancer in Japan with this data. Despite the Japanese filing, BMS has not stated that it has plans to file in the U.S. based on this data, perhaps given the enrollment was limited to Asian populations. Indeed during the discussion, Dr. Lenz of USC Norris Comprehensive Cancer Center took care to point out the molecular differences in gastric cancer between Asian and non-Asian populations citing reported differences in immune signatures.5 Furthermore, subgroup analysis in this trial showed a stronger magnitude of benefit (HR 0.59) in patients with intestinal histologic type (a better prognostic subset that is more common in Asian gastric cancer patients) compared with patients with diffuse histology type (HR 0.82; a worse prognostic subset that is more common in Caucasian gastric cancer patients). Together, this information raise doubts about the translatability of these data in Asian patients to a broader U.S. population. During the question-and-answer portion, however, the issue of U.S. filing based on these Asian data was raised, and some felt that, rather than wait for a new Phase III trial readout, a confirmatory Phase II trial in a U.S. population could warrant filing. Although not raised in yesterday’s session, an alternative scenario could be the National Comprehensive Cancer Network (NCCN) recommending Opdivo for use in relapsed/refractory gastric/GEJ. Such action (NCCN guideline recommendation for U.S. patients based strictly on Asian data) has not previously occurred but might not be entirely outside the realm of possibility given the unmet needs in gastric cancer and the well-established safety profile for Opdivo in other indications, even if balanced against the histologic subgroup data from the Japanese trial. In the absence of accelerated filing or NCCN recommendation, filing with the FDA may need to await the results of the ongoing global Phase III CheckMate 649 trial (NCT02872116) that is being conducted in the first-line setting and is investigating the combination of Opdivo plus Yervoy® (ipilimumab, BMS/Ono), data from which is not expected for several years.
Opdivo is not the only immunotherapy under late-stage development in gastric cancer. Keytruda® (pembrolizumab, MSD) has multiple Phase III trials underway in first-line and relapsed/refractory disease and may be the first immunotherapy agent to enter the gastric cancer market in the United States. Pfizer and Merck KGaA are also developing their PD-L1 inhibitor avelumab in relapsed/refractory gastric cancer. And of course non-immunotherapy approaches are also under late-stage development, including napabucasin (BBI608, Boston Biomedical/Sumitomo Dainippon) in second-line (NCT02178956), Lonsurf® (trifluorothymidine/tipiracil hydrochloride, Taiho) in third-line, GS-5745 (Gilead) in first-line, and Cyramza in first-line. Although the results of this Asian Phase III trial may not have an immediate impact in the U.S. gastric cancer market, these remain highly impactful results globally. Opdivo could gain approval in this indication in Japan as early as late 2017, putting it well-ahead of other competitors in this setting and bringing a new option to this population of high unmet need.
Three presentations to be featured at the 2017 Gastrointestinal Cancers Symposium were singled out as newsworthy at a pre-meeting presscast. The presentations focused on:
PET Scan Guidance (Abstract 1)
Use of PET scans to assess response to induction chemotherapy may allow tailoring of subsequent chemotherapy, vastly improving outcomes for patients with esophageal cancer, according to results of a phase II trial.
“PET scans may prove to be a valuable tool to help oncologists fine-tune the use of chemotherapy for esophageal cancer and maximize the benefits of chemotherapy for each individual patient,” said ASCO Expert Nancy Baxter, MD, moderator of the presscast. “This is heartening evidence for a new approach to treating a disease where innovation is sorely needed.”
Standard treatment for stage II-III esophageal and gastroesophageal junction (GEJ) cancers consists of 5.5 weeks of chemoradiation followed by surgery. Thus far, there is no way to predict which of several chemotherapy regimens will be most effective for an individual patient. The present study utilized PET imaging in 257 patients with stage II-III esophageal and GEJ cancers who were randomized to one of two induction chemotherapy regimens (modified FOLFOX-6 or carboplatin/paclitaxel).
After an initial PET scan at baseline, a second PET scan was obtained following the first few cycles of induction chemotherapy. If the PET scan suggested the regimen was effective, patients continued the same regimen during chemoradiation. If the PET scan suggested that the regimen was not effective, chemotherapy was switched to the other regimen during chemoradiation. Based on PET scan results, switching occurred in 29/129 patients randomized to FOLFOX-6 and 49/128 randomized to carboplatin/paclitaxel.
This study found that PET used to guide therapy after induction chemotherapy achieved improved pathological complete response (pCR) — a surrogate marker for survival in esophageal cancer after induction chemotherapy — compared with previous studies that did not utilize the PET-guided approach.
The pCR rate for non-responding patients was 19% for those who switched to carboplatin/paclitaxel and 17% for those who switched to FOLFOX-6. The pCR rate for all PET non-responding patients taken together was 18%. These pCR rates compare favorably with a 5% pCR rate previously reported in PET nonresponders to induction chemotherapy.
For PET responders, pCR was 26%, and for all patients on study, pCR was 23%.
This is one of the first studies to show the benefit of PET imaging in informing pre-surgery treatment decisions for this type of cancer.
“This strategy [using PET after induction chemotherapy to assess response] can be used in clinical trials to identify the most effective chemotherapy regimens,” said lead author Karyn A. Goodman, MD, University of Colorado School of Medicine, Aurora, CO.
Watch-and-Wait Approach for Rectal Cancer (Abstract 521)
It is possible for strictly selected patients with stage II-IV rectal cancer — that is, patients with no evidence of residual cancer following induction therapy — to forego surgery, according to a large, observational, “real world” study. Using a “watch-and-wait” approach following initial treatment with chemotherapy and/or radiation did not compromise 3-year survival rates.
“Some people with rectal cancer undergo surgery after chemoradiation therapy, even though it may not be necessary,” said study co-author Maxime van der Valk, MD, International Watch and Wait Database (IWWD) Consortium, Leiden University Medical Center, Leiden, the Netherlands. “From the data we have now, it seems that a watch-and-wait may be safe in selected patients with rectal cancer, but it is too soon to say whether this approach should be routinely offered.”
The study was based on an analysis of 679 patients of a total of 802 patients enrolled in the IWWD database (35 institutions from 11 countries). All patients had no signs of residual cancer after induction treatment, as assessed by physical exam, endoscopy, or MRI/CT scans following chemotherapy and radiation. All patients were managed by watch-and-wait care, which included extensive monitoring for recurrence every 3 months by endoscopy, MRI scan, and physical exam for the first 2 years.
At a median follow-up of 2.6 years, 25% of patients underwent delayed surgery due to local recurrence, and distant metastasis was reported in 7%. The 3-year survival rate was 92% among all patients and 87% among those who had a recurrence. These data are comparable with historic data from patients who undergo surgery.
This is not a practice-changing trial, and “watch and wait” is not yet included in treatment guidelines, but it does tell us more about which patients should be considered for this strategy, Dr. van der Walk said.
Dr. Baxter, session moderator, said: “Five years ago, it would have been considered heresy to treat rectal cancer without surgery. Over the past few years, we are beginning to consider this but there are no standard protocols or guidelines. It is an evolving area and patient selection will be critical.”
Physical Activity Associated with Improved Survival in Advanced CRC (Abstract 659)
Even though it may be difficult to exercise with advanced colorectal cancer (CRC), moderate physical activity appears to be life-extending, according to a smaller trial embedded in a large phase III trial of 1,231 patients designed to evaluate chemotherapy for metastatic CRC.
Prior to starting chemotherapy, patients reported their physical activity level on a questionnaire. The researchers determined the level of physical activity per week for each patient. Patients who were engaged in 30 or more minutes each day of moderate physical activity (i.e., walking, cleaning, or gardening) had a 19% reduction in mortality and a 16% reduction in disease progression compared with those who spent the least amount of time engaging in moderate physical activity (i.e., 30 minutes of moderate physical activity per week).
Engaging in the physical activity also was linked to improved survival; patients who walked 4 or more hours per week had a greater than 20% improvement in overall survival, and those who participated in 5 or more hours a week of nonvigorous physical activity (i.e. yoga or walking) had a 25% improvement in overall survival.
“These findings suggest that as little as 30 minutes a day of moderate physical activity may improve outcomes,” said lead author Brendan John Guercio, MD, resident at Brigham & Women’s Hospital in Boston, MA. “While exercise is by no means a substitute for chemotherapy, patients can experience a wide range of benefits from as little as 30 minutes of exercise a day.”
No association was found between vigorous physical activity and cancer outcomes, but the numbers of patients engaging in vigorous physical activity were too small to show statistical significance.
This is one of the first studies to show a link between level of physical activity in patients with CRC and distant metastases. Prospective studies are needed to confirm these associations.
The 2017 Gastrointestinal Cancers Symposium is jointly sponsored by the American Gastroenterological Association (AGA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Surgical Oncology (SGO) and will take place January 19-21, 2017, at the Moscone Convention Center in San Francisco.
by John McCleery