Patients with metastatic colorectal cancer (mCRC) are typically treated at some point with at least one angiogenesis inhibitor. According to Kantar Health’s CancerMPact® Treatment Architecture U.S. data, Avastin® (bevacizumab, Genentech/Roche) is offered to approximately one-half of KRAS wild-type chemotherapy-naïve patients and three-quarters of KRAS mutated chemotherapy-naïve patients in the first-line setting. In the second- or third-line setting, patients might be treated with Avastin, Zaltrap® (ziv-aflibercept, Sanofi) or Stivarga® (regorafenib, Bayer/Onyx). Given data from the 2015 ASCO Gastrointestinal Cancers Symposium, Cyramza® (ramucirumab, Eli Lilly) may soon be added to the list of agents for second- or third-line therapy.
The use of Cyramza in this setting was examined in the Phase III RAISE trial, which enrolled 1,050 mCRC patients who had progressed during or after first-line Avastin, oxaliplatin and a fluoropyrimidine and randomized them to treatment with FOLFIRI q2w or FOLFIRI plus Cyramza 8 mg/kg q2w.1 Treatment would continue until disease progression or unacceptable toxicity. The trial roughly included similar numbers of KRAS wild-type and mutant patients, and this status was a stratification factor for the trial.
RAISE met its primary endpoint of improving overall survival (OS) as the addition of Cyramza reduced the risk of death by 16% (median OS: 13.3 months versus 11.7 months, HR 0.84, p=0.0219). Both KRAS wild-type and mutant patients achieved benefit, although neither subgroup analysis was statistically significant. RAISE also met a secondary endpoint of progression-free survival (median PFS: 5.7 months versus 4.5 months, HR 0.79, p=0.0005) but did not significantly improve the response rate (13.4% versus 12.5%, p=0.6336) or disease control rate (74.1% versus 68.8%, p=0.0587). The toxicity profile was not surprising given Cyramza’s current approvals in both relapsed/refractory gastric cancer and non-small cell lung cancer (NSCLC). Common Grade 3 or higher toxicities that were significantly increased with Cyramza included neutropenia (38.4% versus 23.3%), fatigue (11.5% versus 7.8%), hypertension (10.8% versus 2.8%) and thrombocytopenia (3.0% versus 0.8%).
Given the statistically significant improvement in overall survival, Cyramza should ultimately be approved by the U.S. Food and Drug Administration (FDA) for use in this setting. Although the degree of benefit in RAISE borders on clinically meaningful (1.6-month OS benefit, HR 0.84, p=0.0219), the FDA approved it in December for use in second-line NSCLC based on similar borderline benefit in the REVEL trial2 (1.4-month OS benefit, HR 0.857, p=0.0235). In both of these trials, the magnitude of benefit fell short of the Recommended Targets for Meaningful Clinical Trial Goals that were put forth by an ASCO working group in early 2014 for these two indications.3 Nevertheless, the FDA approved Cyramza in NSCLC and may do the same in mCRC given the demonstrated OS benefit.
However, earning regulatory approval may be the least of Cyramza’s difficulties for gaining future utilization in mCRC. Once approved, Cyramza will compete in the second-line setting with Avastin and Zaltrap as noted above. Both of these agents have been tested in patients pretreated with Avastin. Second-line Avastin in Avastin pretreated patients was directly examined in the Phase III ML 18147 trial, colloquially referred as TML (for Treatment across Multiple Lines).4 TML evaluated the addition of Avastin to chemotherapy (either oxaliplatin- or irinotecan-based). Zaltrap was approved for second-line use based on data from the Phase III VELOUR study, which evaluated the addition of Zaltrap to FOLFIRI in second-line patients. Subgroup analysis in patients who were treated with first-line Avastin has been published.5 As shown in the table below, all three anti-angiogenic agents show similar underwhelming (>0.80) hazard ratios for OS.
|Efficacy Comparisons Between Avastin, Zaltrap and Cyramza in 2nd-Line mCRC|
|TML (Avastin-Pretreated3)||VELOUR (Prior Avastin Subgroup Only4)||RAISE (Avastin-Pretreated1)|
|Placebo + CT (n=410)||Avastin + CT (n=409)||HR (p-value)||Placebo + FOLFIRI (=187)||Zaltrap + FOLFIRI (n=186)||HR (p-value)||Placebo + FOLFIRI (n=525)||Cyramza + FOLFIRI (n=525)||HR (p-value)|
|Median OS||9.8||11.2||0.81 (p=0.0211)||11.7||12.5||0.862 (NP)||11.7||13.3||0.84 (p=0.0219)|
|Median PFS||4.1||5.7||0.68 (p<0.0001)||3.9||6.7||0.661 (NP)||4.5||5.7||0.79 (p=0.0005)|
|CT: Chemotherapy; NP: Not provided|
Not only is Cyramza attempting to compete with agents that have been approved for this setting since 2012 (Zaltrap) and 2013 (Avastin for use in Avastin-pretreated CRC), but it may be doing so with a pricing problem. One physician in attendance at the ASCO GI presentation directly asked why he should offer Cyramza if it costs “twice as much” as Avastin. Estimated costs of these agents support this claim: Avastin per cycle, assuming the use of the lower dosage of 5 mg/kg q2w, is approximately $2,400. Cyramza is expected to cost $5,900 per cycle of therapy based on the dose used in this trial and its current price for approved indications. This is eerily reminiscent of difficulties for Zaltrap, when several physicians from the Memorial Sloan-Kettering Cancer Center wrote an opinion piece in The New York Times stating they would not provide Zaltrap to their patients since it was more than twice the cost of Avastin; the negative publicity associated with the article forced Sanofi to drop its pricing for Zaltrap.
The situation doesn’t improve for Cyramza even if it is considered in later lines of therapy. Not only would Cyramza need to compete with the anti-angiogenic agent Stivarga, which was approved in 2012 by the FDA, but it also will likely need to compete against TAS-102 (Lonsurf® in Japan, Taiho Oncology), a formulation of two antimetabolic agents that met its primary endpoint of OS in the Phase III RECOURSE study.6 The FDA has granted TAS-102 a fast-track designation, and Taiho confirmed that it had already initiated a rolling submission for approval.
Cyramza faces tough hurdles ahead given the data presented at the ASCO Gastrointestinal Cancers Symposium: activity comparable to other anti-angiogenic agents that are already approved in the same setting, and at a potentially higher cost. With these hurdles, it is hard to imagine Cyramza “RAISEing” the bar in second-line CRC in the near future.
1. Tabernero et al.; Abstract 512, 2015 ASCO Gastrointestinal Cancers Symposium
2. Perol, et al.; Abstract LBA8006, ASCO 2014
3. Ellis, et al.; J Clin Oncol, 32(12): 1277-1280, 2014.
4. Bennouna, et al.; Lancet Oncol, 2013
5. Tabernero, et al.; Eur J Cancer, 2014
6. Yoshino, et al.; Abstract O-0022, 2014 ESMO World Congress on Gastrointestinal Cancer.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Arnold DuBell, Ph.D., M.B.A, Consultant, Clinical and Scientific Assessment, Kantar Health
Designated as a “breakthrough therapy” by the FDA for both advanced and unresectable malignant melanoma and advanced non-small cell lung cancer (NSCLC), and approved by the U.S. Food and Drug Administration (FDA) in September 2014 for advanced pretreated metastatic melanoma, the immune checkpoint inhibitor Keytruda® (pembrolizumab, Merck) has also shown promise for several other indications including (but not limited to) head and neck cancer, Hodgkin’s lymphoma and triple-negative breast cancer (TNBC).
Given Keytruda’s remarkable performance as an antitumor agent in several advanced/metastatic diseases, the therapeutic potential of this promising new drug is now being explored in the context of advanced gastric cancer. In a keynote address on Thursday, Jan. 15 at the 2015 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, an updated cohort analysis of 39 patients with either recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction from the Phase 1b KEYNOTE-012 study1 was presented. For this specific analysis, only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were included. Patients were heavily pretreated; 67% of the patients had received two or more prior therapies. Patients were given 10 mg/kg Keytruda every two weeks for up to 24 months or until complete response, progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR), and secondary endpoints were duration of response, progression-free survival (PFS) and overall survival (OS).
Keytruda achieved a favorable ORR of 22% by central review and 33% by investigator review. This differs only slightly from that presented at the European Society for Medical Oncology (ESMO) 2014 Congress (30.8% ORR by investigator review).2 Responses were similar between Asian and non-Asian patients. The median time to response was eight weeks, and the median response duration was 24 weeks. The six-month PFS rate was 24%, and the median PFS was 1.9 months. The six-month OS rate was an impressive 69%, and the median OS was not yet reached. Patients had a median follow-up duration of 8.8 months, and 33% remained on therapy as of November 2014. Although the data were very preliminary, a trend toward an association between higher levels of PD-L1 expression and ORR (p=0.102), PFS (p=0.162) and OS (p=0.124) was observed. Only four patients experienced Grade 3 or higher drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia and pneumonitis (2.6% each); one of these adverse events (hypoxia) resulted in patient death.
To date, the treatment landscape for advanced or relapsed gastric cancer has proven to be relatively bleak. Prior to the approval of the VEGFR-2-targeted therapy Cyramza® (ramucirumab, Eli Lilly), there were no approved targeted agents for the treatment of relapsed gastric cancer, and physicians relied on fluoropyrimidine- or taxane-based chemotherapy. Cyramza was approved in the U.S. and Europe based on results from the REGARD and RAINBOW trials. In REGARD, Cyramza was associated with an OS of 5.2 months versus 3.8 months for placebo (HR 0.776, p=0.0473) in patients previously treated with first-line platinum- or fluoropyrimidine-based therapy. In addition, the six-month OS rates were 41.8% in patients treated with Cyramza versus 31.6% in the placebo group.3 RAINBOW compared paclitaxel ± Cyramza as a second-line therapy; the addition of Cyramza to paclitaxel significantly extended median OS (9.6 months versus 7.4 months, HR 0.81, p=0.017). The six-month and 12-month OS rates for Cyramza plus paclitaxel were 72% and 40%, respectively, compared with 57% and 30% for paclitaxel alone.4
The results of the KEYNOTE-012 gastric cancer cohort analysis highlight the promising antitumor activity and manageable toxicity of Keytruda in advanced gastric cancer. While there are caveats to comparing trials directly, patients treated with Keytruda monotherapy had a similar six-month OS (69%), as did patients treated with Cyramza + paclitaxel (72%); however, recall that the patients on Keytruda were more heavily pretreated. Building on this signal, Merck has announced plans to initiate a Phase II trial (KEYNOTE-059; NCT02335411) to evaluate Keytruda or Keytruda plus cisplatin and 5-FU in 270 patients with recurrent or metastatic gastric and gastroesophageal junction adenocarcinoma. The primary outcomes will be safety and response. This study will provide some important insights on the activity and safety of Keytruda, including its use in combination with chemotherapy, the importance of PD-L1 as a biomarker, and the role of Keytruda in both first-line and relapsed settings. Findings from KEYNOTE-012 should provide valuable to inform future Phase III trial design.
However, as with other tumor types, other manufacturers of PD-1 inhibitors have announced plans to compete in this space. A new Phase III trial (NCT02267343) was initiated in October 2014 to compare Opdivo® (nivolumab, ONO-4538/BMS-936558, Bristol-Myers Squibb/Ono Pharmaceuticals) versus placebo in 480 previously treated Japanese patients with unresectable advanced or recurrent gastric and gastroesophageal junction cancer. This trial will not limit patient enrollment by PD-L1 biomarker status. The primary endpoint will be OS, and secondary endpoints will include PFS, ORR and safety. To date, there are no known late-stage trials of Opdivo in Western gastric cancer patients, but it can be assumed that trials may be initiated in the near future. As in melanoma, Opdivo may ultimately have a first-to-market advantage over Keytruda in gastric cancer in Japan, but Keytruda may have a leg up in the Western markets for this indication.
Along with immunotherapy, other targeted therapies are planning Phase II trials, including Stivarga® (regorafenib, Bayer, NCT01913639) and AMG 337 (Amgen, NCT02016534). Eli Lilly has also announced plans for another Phase III trial for Cyramza (RAINFALL, NCT02314117), which will compare capecitabine plus cisplatin with or without Cyramza in 616 newly diagnosed gastric or gastroesophageal junction cancer patients.
As with other tumors, the competitive landscape for gastric could dramatically change within the next several years given the data presented. These data are certainly at an early stage, but the high response rates and preliminary OS data justify the excitement associated with the PD-1 inhibitors and add gastric cancer to the growing list of tumors in which immuno-oncology may play a significant role.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Elizabeth Clarke, Ph.D., Analyst, Clinical and Scientific Assessment, Kantar Health
Four studies presented at a media telebriefing prior to the Gastrointestinal Cancers Symposium 2015 highlighted key findings in colorectal cancer. The findings will be presented January 15-17, 2015, in San Francisco.
The studies were culled from more than 800 abstracts that will be viewed by 3,200 specialists and surgical, medical and radiation specialists from around the world.
Survival Advantage Shown for Ramucirumab Plus Chemotherapy in Second-Line CRC Treatment
The phase 3 international RAISE trial (Abstract 512) found that ramucirumab extends survival when given with chemotherapy to metastatic colorectal cancer patients who progress on treatment.
The RAISE study randomized 1,072 patients who progressed after first-line therapy to treatment with FOLFIRI (leucovorin, fluorouracil, irinotecan) plus ramucirumab or placebo. Response rates were similar between the two arms—13.4% with ramucirumab; 12.5% with placebo—but ramucirumab significantly improved both progression-free and overall survival.
Median time to disease progression in patients receiving ramucirumab plus FOLFIRI was 5.7 months compared with 4.5 months in the placebo arm (HR=0.79; P=0.0005). Median overall survival was 13.3 months and 11.7 months (HR=0.84; P=0.0219), respectively.
The regimen was well tolerated, though the addition of ramucirumab increased the incidence of Grade 3-4 neutropenia, fatigue, diarrhea, and hypertension.
“Though the rate of neutropenia was higher, the rate of febrile neutropenia, the clinically significant toxicity, was similar, 3.6% versus 2.7% in the placebo arm,” said Josep Tabernero, MD, Vall d’Hebron Institute of Oncology in Barcelona, Spain. According to Dr. Tabernero the adverse events were manageable.
The study validates angiogenesis as an important target in colorectal cancer. Other angiogenesis inhibitors approved in this malignancy include bevacizumab, ziv-aflibercept, and regorafenib.
Dr. Tabernero pointed out that the study population was representative of patients seen in everyday practice. He cautioned, however, that the findings should not be extrapolated to other regimens used in colorectal cancer. Ramucirumab is currently FDA-approved in gastric and non-small lung cancer.
Commenting on the study, moderator Smitha S. Krishnamurthi, MD, Associate Professor of Medicine at Case Western Reserve University School of Medicine, Cleveland, acknowledged that improvements in 1 to 2 months in progression-free and overall survival appear modest. However, she said, “We want to offer patients all we can, because these agents [biologics] tend to be well tolerated and they can be combined with chemotherapy.”
Bevacizumab Works Best Combined with Intensive Chemotherapy
Updated results from the phase 3 TRIBE study (Abstract 657) conducted in Italy indicate that bevacizumab is more effective in metastatic colorectal cancer when combined with the FOLFOXIRI regimen than FOLFIRI. FOLFOXIRI plus bevacizumab extended overall survival by 4 months and doubled the 5-year survival rate over the control arm, reported Chiara Cremolini, MD, of the Tuscan Tumor Institute in Pisa.
In the U.S., FOLFOX (leucovorin, fluorouracil, oxaliplatin) and FOLFIRI (leucovorin, fluorouracil, irinotecan) are more commonly used than FOLFOXIRI, which adds oxaliplatin to the FOLFIRI regimen.
The study evaluated 508 patients randomized to bevacizumab plus either FOLFOXIRI or FOLFIRI for 6 months, after which they received maintenance bevacizumab with 5-FU/leucovorin. After a median follow-up of about 4 years, median overall survival was 29.8 months in the FOLFOXIRI arm versus 25.8 months in the FOLFIRI arm (HR=0.80; P=0.030).
“Looking at the final part of the shape of the survival curves, we see that the benefit of FOLFOXIRI plus bevacizumab increases over time, and the estimated 5-year survival is 24.9% versus 12.4%, which is double to that of FOLFIRI plus bevacizumab…Based on these results, FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment of metastatic colorectal cancer,” Dr. Cremolini concluded.
The study found a higher incidence of Grade 3-4 diarrhea, mucositis, neuropathy, and neutropenia, with the FOLFOXIRI regimen, but no increase in febrile neutropenia and or serious adverse events of treatment-related deaths. The incidence of severe neuropathy, which is a concern with oxaliplatin, was only 5%.
Dr. Cremolini acknowledged that the regimen, which tends to be more difficult and leads to more dose reductions and delays, “is not a regimen for every patient.” In her opinion, it is probably not suitable for patients older than age 75 or younger patients with poor performance status.
Dr. Krishnamurthi indicated that in the U.S, the “uptake was not high, when the data first came out, because we are already combining chemotherapy with bevacizumab,” however, with more evidence of efficacy and safety, she predicted, “I think we will see more use of FOLFOXIRI with bevacizumab.”
High Vitamin D Associated with Improved Survival
Newly diagnosed colorectal cancer patients with high vitamin D levels prior to treatment live longer than those with the lowest levels, according to a prospective analysis of data from a phase 3 study (Abstract 507).
The study adds to a growing body of evidence that vitamin D has an anti-tumor effect. Randomized studies are now underway to confirm the benefit of vitamin D supplementation before and after a cancer diagnosis, said Kimmie Ng, MD, MPD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.
“The ultimate goal is to translate this research into an effective intervention for patients,” she said.
Dr. Ng and colleagues measured the serum levels of vitamin D (25-hydroxyvitamin D) in 1,043 patients enrolling in CALGB 80405, the phase 3 trial evaluating three different first-line treatments for advanced colorectal cancer. Patients’ vitamin D levels ranged from a mean low of 8 ng/mL to a mean high of 27.5 ng/mL. The average for all patients was 17.2 ng/mL, which is below the recommended healthy range of 20 to 30 ng/mL. Few patients report taking vitamin D supplements.
Divided into quintiles according to their baseline level, and being adjusted for other prognostic factors for survival as well as healthy behaviors, patients with the highest levels of vitamin D had a median overall survival of 32.6 months, compared with 24.5 months for those in the lowest quintile (HR=0.67; P=0.002).
Higher vitamin D levels were also associated with longer time to disease progression, 12.2 months vs. 10.1 months (HR=0.80; P=0.02). The benefit was seen across the three treatment arms and did not differ by KRAS status, nor was benefit ameliorated when other prognostic factors were adjusted for.
Despite the encouraging results, Dr. Ng said it is premature to recommend vitamin D as a treatment for colorectal cancer. She noted that the findings do not indicate that raising a low baseline vitamin D level will improve outcomes, only that baseline levels were associated with different outcomes.
“Watch and Wait” is Acceptable for Some Rectal Cancer Patients
Some rectal cancer patients who achieve a complete response to neoadjuvant chemoradiation may not need surgery, according to a retrospective review of data on 145 patients with stage I-III rectal cancer.
Philip Paty, MD, of Memorial Sloan Kettering Cancer Center, New York, said the results should “encourage more doctors to consider a ‘watch and wait’ approach in patients with clinical complete response as an alternative to immediate rectal surgery, at least for some patients.”
Avoidance of surgery would allow patients to preserve rectal function, which is very important to patients, he explained. “Most patients who qualify for this approach are very interested in it,” he said.
The study was a retrospective look at 73 patients who achieved a clinical complete response after neoadjuvant chemoradiation and were treated with a non-operative management approach (with frequent monitoring, every 3 months for the first 1.5 years). Their outcomes were compared with those of 72 patients who achieved a pathologic complete response (pCR) and underwent resection.
Of the 73 patients who were observed, 74% achieved a durable and sustained clinical response and no surgical intervention was required. Nineteen patients (19%), however, had local regrowth of tumor, and all had successful salvage surgery.
Altogether, 98% of patients achieved local control (one patient had a recurrence after resection of the tumor regrowth), and 77% had rectal preservation. The disease-specific and overall survival rates were similar between the two groups, suggesting that the nonoperative approach for these patients did not compromise outcomes.
“We set the bar very high, and found that nonoperative management appears to compare favorably,” said Dr. Paty.
He acknowledged that “practicing ‘watch and wait’ can be difficult for surgeons” but this approach is being increasingly accepted.
“Centers are adopting it, and many leaders in clinical trials of rectal cancer recognize that this option is not only reasonable, but perhaps it is necessary to inform patients that it is an option,” he said.
Complete responses are typically observed in up to 50% of patients with stage I disease and 30% to 40% with stage II-III tumors, making these patients candidates for nonoperative management.
Dr. Krishnamurthi indicated she would feel better about observing these patients once the investigators can report longer follow-up.
By Caroline Helwick