신장 암에 효과적인 표적요법-면역요법의 결합
2019년 3월 19일 : 국립암연구소 제공
내용요약 :
. 두 건의 대형 임상시험의 결과가 향후의 치료의 환경을 바꿀 것.
- 표적요법제 인리타(악시티닙) + 면역요법제 바벤시오(아벨루맙)의 결합요법의 결과가
양호함.
- 인리타 + 키트루다(펨브롤리주맙)의 결합요법의 결과는 더욱 양호함.
- 기존의 표적요법제 수텐트 단독 치료보다 결과가 양호
. 지난 12년간 신장암 치료 과정에 생긴 두 번의 혁명.
- 1차 혁명 : 10여 년 전 표적요법의 출현(수텐트, 인리타). 기존의
인터페론 알파보다 월등 (1년 미만의 생존을30개월로 연장).
- 2차 혁명 : 2015년 바벤시오(아벨루맙)와 키트루타(펨브롤리주맙) 등의 출현으로
신장암 치료의 가능성을 크게열다. (30개월의 생존율을 3년으로 연장)
- 2018년 : 미국 FDA는 또 다른 면역관문억제제 옵디보(니볼루맙) + 예르보이
(이필리무맙)의 결합요법 승인
. 현재까지 신장암 치료법 중 키트루다 + 인리타의 결합요법이 가장 인상적.
. 어떤 치료가 어떤 환자에게 더 효과적인지 결론을 최종 결론을 내리려면 다소의 연구와
시간이 필요.
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두 번의 대규모 임상 실험의 결과 덕분에 신장 암의 신규 환자들의 초기 치료법은 크게 바뀔 것으로 예상된다.
두 연구에서, 면역 관문 억제제라고 불리는 두 종류의 면역 요법제(바벤시오. 키트루다)와 표적 요법제 인리타(악시티닙)를 조합한 결합 치료(바벤시오+인리타, 키트루다=인리타)는 지금까지의 1선 요법의 표준요법인 수텐트(수니티닙)만으로 하는 치료보다 진행성 신장 암 환자에게 더 좋은 결과를 이끌어내었다.
2건의 3상 임상시험 결과는 지난 달 미국 임상 종양학회 비뇨생식기 암 심포지엄(GU ASCO)에서 보고되었으며, 동시에 뉴잉글랜드 의학저널(NEJM)에도 발표되었다.
식품의약품안전청(FDA)은 이미 신장암에 걸린 사람들을 위한 초기 치료법, 즉 첫 번째 치료법으로 하나의 면역요법 결합을 승인했다. 그리고 이 새로운 자료를 근거로, 몇몇 전문가들은 이 환자들에 대한 추가 승인이 곧 있을 것이라고 말했다.
"흥미 있는 자료들이 많고, 치료계의 환경이 빠르게 변하는 중“이라고 신장암 연역요법 연구에 관여를 해 온 베스 이스라엘 디콘리스 메디컬 센터 종양학 책임자인 데이비드 맥더모트 박사가 말했다.
진행성 신세포 암 치료전략의 진화
프랑스의 구스타브 루시 암 캠퍼스의 베르나르 에스쿠디에 박사는 지난 12년간 전이성 신세포암 치료는 "두 번이나 혁명적 변화를 겪었다"고 NEJM의 두 건의 논문에 게재했다.
첫 번째 큰 변화는 10여 년 전에 표적요법제의 출현과 함께 일어났다. 수텐트가 먼저 나왔고, 이어서 인리타와 이와 유사한 약물이 개발되었다. 이것들은 신장 암에 중요한 역할을 하는 혈관의 내피세포 성장인자라는 단백질을 차단한다.
이 표적요법은 당시 1선 치료법이었지만 소수의 환자들에게만 효과가 있고 심각한 부작용을 가지고 있는 치료법인 인터페론 알파보다 더 효과적인 치료법이었다.
2015년에 두 번째 큰 변화가 일어났는데, 그 때 에스코디에 박사가 기록하기를 면역 관문 억제제 옵디보가 초기 치료 후 진행된 신장 암 환자들에게 효과가 있는 것으로 나타났고 얼마 안 되어 이런 환자에 대한 표준 요법이 되었다.
2018년 FDA는 대형 임상실험 결과 수텐트로 치료를 받은 환자에 비해 훨씬 양호한 생존율을 보인 2가지의 면역관문 억제제인 옵디보와 예르보이의 결합을 초기 치료제로 승인했다.
표적요법과 면역요법을 결합하기
새로운 실험은 독자적으로 신장암 치료에 효과가 있었던 혈관 내피세포 성장인자 억제제인리타(액시티닙)와 두 종류의 면역관문억제제(바벤시오, 키트루다)를 결합하는 새로운 치료 시도를 했다.
이 연구는 서로 다른 면역 치료제를 사용 것 외에는 매우 유사했다. 두 실험에는 이전에 치료를 받은 적이 없는 투명세포 신세포 암 환자 800명 이상이 등록했다.
주로 유명 제약사 화이자의 자금 지원을 받은 첫 번째 연구에서는 인리타(악시티닙)와 결합한 면역관문억제제 바벤시오(아벨루맙)를 테스트했고, 그 결합치료를 받은 환자들이 수텐트(수니티닙)로 치료받은 환자에 비해 무 진행 생존이 길었다.
머크 사가 주로 후원한 두 번째 연구에서는 인리타(악시티닙)와 함께 면역관문억제제 키트루다(펨브롤리주맙)를 테스트했고 참가자의 전체 생존뿐만 아니라 수텐트 (수니티닙) 치료에 비해 무 진행 생존도 상당히 개선된 것으로 나타났다.
바벤시오(아벨루맙)-인리타(악시티닙) 연구의 선임 저자인 토니 추에이리(M.D) 박사가 설명하기를 "인리타는 신장 암에 작용하고 있으며, 바벤시오도 신장 암에 작용하는 계열의 약물에 속한다. 그러니까 효과가 있는 두 가지 약을 결합하는 것." 이다.
이전에, 더 소규모 연구에서 인리타가 바벤시오 또는 키트루다와 결합될 수 있다는 것을 보여주었는데, 그 용량은 간이 견딜 수 있고 수치의 독성을 유발하지 않는 최대 허용치였다. 이와는 대조적으로 수텐트와 면역관문억제제를 결합한 것은 심각한 부작용을 초래했다고 추에이리 박사는 말했다.
키트루다+인리타 연구의 수석 조사관인 브라이언 리니 박사는 인리타는 수텐트보다 더 구체적으로 혈관 내피성장인자를 표적으로 삼는고 설명했다. 리니 박사는 "인리타는 더 강력하고 환자가 더 잘 견디며 더 나은 결합 파트너였다"고 말했다.
그러나 맥더모트 박사는 "지금까지 진행된 신장 암 치료 시도 중 가장 인상적인 데이터는 키트루다+인리타의 연구 결과"라고 말했다.
런던 바트 암 연구소의 토머스 파워스 연구 조사원은 ASCO 회의에서 연구 결과를 발표하면서 키트루다와 인리타의 조합은 "모든 핵심 환자군에서 성능이 월등히 뛰어났다"고 말했다. 거의 13개월의 중간 추적 검사에서, 킽트루다와 인리타로 치료 받은 환자의 약 90%가 여전히 살아있었던 반면에 수니티닙만으로 치료 받은 환자는 78%가 살아있었다.
바벤시오를 인리타와 결합한 시험 시험에서, 이 결합치료를 받은 환자들은 무 진행 생존(13.8개월 대 8.4개월)이 수티티닙 단독치료보다 더 길었고, 수텐트 단독치료 환자에 비해 종양이 축소(객체적 반응)의 가능성이 더 높았다. 발표 당시, 환자의 후속 관찰 기간은 전체 생존에 개선이 있는지 여부를 판단하기에 충분하지 않았다.
"올해는 전체 생존을 평가할 것"이라고 추에이리 박사는 말했다.
두 연구는 환자의 후속 관찰에서 생존과 장기적인 부작용을 계속 모니터할 것이라고 두 시험의 조사관들이 말했다. 부작용의 비율은 두 시험의 치료 그룹이 공히 높았고, 고혈압과 설사가 가장 흔한 부작용 중 하나였다.
신장 암 치료 환경의 변화
맥더모트 박사는 결합요법이 1선 치료제로서 혈관 상피세포 성장인자 억제제 단독보다 우수하다는 것이 "본질적으로 증명되었다"고 말했다. 결합요법은 비용이 많이 들고 부작용이 더 많이 발생하긴 하지만 분명한 장점이 있다고 학자들은 보았다.
어떤 결합치료가 환자에게 최선일지 아직 확실하지 않다고 리니 박사는 말했다. "아직 미묘한 점이 있다. 정답을 아직 알 수 없다. 우리는 이 문제를 향후 몇 년 동안 해결하기를 희망한다."고 리니 박사가 말했다.
바벤시오-인리타 연구의 수석 조사관이었던 로버트 모처 박사는 "현재 세 가지 복합 치료법이 1차 치료제로 자리 잡았다"고 말했다. 이러한 새로운 결합이 FDA 승인을 받는다고 가정하면, 환자의 삶의 질과 안전성, 완전반응을 경험하는 환자의 비율과 같은 요소들이 어떤 치료법을 사용할지에 영향을 미칠 것으로 예측한다.
수텐트(수니티닙) 같은 약물이 등장하기 전에 신장 암은 예후가 좋지 않았고 전체 생존율은 1년도 채 되지 않았다. 혈관 상피세포 성장인자(VEGFR) 억제제를 사용함으로써, 중위수 생존기간은 약 30개월로 개선되었다.
그리고 이제 면역요법 생존 기간을 3년 이상으로 연장하는데 도움을 주고 있다.
기존의 치료법은 결국 대부분의 진행성 신장 암 환자들에게 효과가 없어지고, 병이 진행되기 때문에 계속해서 차례대로 치료를 해야 한다.
다른 치료 순서를 연구하는 것 외에도, 연구원들은 어떤 치료가 다른 사람들에게 더 효과적일지 예측하는 데 도움이 될 수 있는 종양이나 바이오마커의 특징의 확인 가능 여부를 조사하고 있다고 Motzer 박사는 말했다.
"궁극적으로 환자에게 가장 중요한 것은 이런 새로운 접근방식이 장기적인 생존에 미치는 영향이다. 즉 얼마나 많은 환자들이 관해가 되었는가? 실제로 신장 암을 치료한 환자가 있는가?" 등이며, 그런 것들을 알아내려면 시간이 좀 걸릴 것."이라고 모쳐 박사가 말했다.
또 신장 암에 대한 새로운 치료법 중 일부는 수술로 치료할 수 있는 암의 진행이 덜된 일부 환자들, 특히 3기 암 환자들에게 보조 요법으로 테스트를 하고 있다.
한 보조 임상시험에서 현재 환자를 등록받고 있으며 의사와 환자들이 가능한 임상시험에 참여하도록 권장했다고 맥더모트 박사가 말했다.
Targeted Therapy–Immunotherapy Combinations Effective for Advanced Kidney Cancer
March 19, 2019, by NCI Staff
Results from two large clinical trials are expected to change the initial treatment for many people with newly diagnosed advanced kidney cancer.
In both studies, combination treatments that included a type of immunotherapy called an immune checkpoint inhibitor and the targeted therapy axitinib (Inlyta) led to better outcomes for patients with advanced kidney cancer than treatment with sunitinib (Sutent) alone, the standard of care for first-line therapy.
Results for the two phase 3 trials were reported last month at the American Society of Clinical Oncology Genitourinary Cancers Symposium (GU ASCO) in San Francisco and simultaneously published in the New England Journal of Medicine (NEJM).
The Food and Drug Administration (FDA) has already approved one immunotherapy combination as an initial, or first-line, treatment for people with advanced kidney cancer. And, based on these new data, several experts on the disease said further approvals for these patients are likely to be forthcoming.
“There’s a lot of exciting data. The treatment landscape is changing quickly,” said David McDermott, M.D., chief of medical oncology at Beth Israel Deaconess Medical Center, who has been involved in kidney cancer immunotherapy studies.
Evolving Treatment Strategies for Advanced Renal-Cell Cancer
In the last 12 years, the treatment of metastatic renal-cell cancer “has been revolutionized twice,” wrote Bernard Escudier, M.D., of the Gustave Roussy Cancer Campus in France, in an editorial accompanying the two papers in NEJM.
The first big change occurred more than a decade ago with the advent of targeted therapy. Sunitinib and, later, axitinib and similar drugs were developed that block a protein called the vascular endothelial growth factor receptor (VEGFR), which plays an important role in kidney cancer.
These targeted treatments were shown to be more effective than what was then the first-line treatment, interferon alpha, a treatment that worked only in a small number of patients and had serious side effects.
A second big change came in 2015, Dr. Escudier wrote, when the immune checkpoint inhibitor nivolumab (Opdivo) was shown to be effective in patients with advanced kidney cancer that had progressed after their initial treatment, soon after becoming the standard of care for these patients.
In 2018, FDA approved the combination of nivolumab and ipilimumab (Yervoy), two immune checkpoint inhibitors, as an initial treatment for the disease, after a large clinical trial showed that the approach led to better survival compared with patients treated with sunitinib.
Combining Targeted Therapy and Immunotherapy
The new trials took a different approach, combining the two strategies—a VEGFR inhibitor (axitinib) and an immune checkpoint inhibitor—that have been effective in treating kidney cancer on their own.
The studies used different immunotherapy agents but were otherwise very similar. Both trials enrolled more than 800 patients with previously untreated advanced clear-cell renal-cell carcinoma.
One study, funded primarily by Pfizer, tested the immune checkpoint inhibitor avelumab (Bavencio) in combination with axitinib, and showed that patients treated with the combination lived longer without their disease worsening (progression-free survival) compared with patients treated with sunitinib.
The second study, funded primarily by Merck, tested the immune checkpoint inhibitor pembrolizumab (Keytruda) along with axitinib and showed a significant improvement in how long participants lived overall (overall survival), as well as progression-free survival compared with sunitinib.
Toni Choueiri, M.D., of the Dana-Farber Cancer Institute, a senior author on the avelumab–axitinib study, explained, “We built the combination based on the fact that axitinib works in kidney cancer, and avelumab is in a class of agents that also work on kidney cancer. So you bring together two drugs that work.”
Earlier, smaller studies had shown that axitinib could be combined with either avelumab or pembrolizumab, all at full dose without causing unacceptable levels of toxicity in the liver. In contrast, combining sunitinib with an immune checkpoint inhibitor caused severe side effects, Dr. Choueiri said.
Axitinib targets VEGFR more specifically than sunitinib does, explained Brian Rini, M.D., of the Cleveland Clinic, a lead investigator on the pembrolizumab–axitinib study. “Axitinib is more potent and better tolerated, and made a better combination partner,” Dr. Rini said.
But some of “the most impressive data to date” for treating advanced kidney cancer are from the pembrolizumab–axitinib study, Dr. McDermott said.
The combination of pembrolizumab and axitinib “broadly out-performed sunitinib in all key [patient] groups,” said study investigator Thomas Powles, M.D., of the Barts Cancer Institute in London, in his presentation of the study results at the ASCO meeting. At a median follow-up of nearly 13 months, approximately 90% of patients treated with pembrolizumab and axitinib were still alive, compared with 78% of patients treated with sunitinib.
In the trial testing avelumab in combination with axitinib, patients treated with the drug combination had longer median progression-free survival (13.8 months versus 8.4 months) and were more likely to have their tumors shrink (objective response) compared with patients treated with sunitinib. At the time of publication, the patient follow-up was not long enough to determine whether there is an improvement in overall survival.
“This year we will assess overall survival,” Dr. Choueiri said.
Follow-up of patients in both studies will continue to monitor survival and long-term side effects, investigators from both trials said. Rates of side effects were high in all treatment groups in both trials, with high blood pressure and diarrhea being among the
most common side effects.
The Shifting Treatment Landscape for Kidney Cancer
Combination treatments have “essentially been proven” to be superior to VEGFR inhibition alone as first-line therapy, Dr. McDermott said. Combination treatments have clear benefits, although they are more costly and cause more side effects, he added.
As for which combination treatment will be the best for which patients, that’s still unclear, Dr. Rini said. “There are subtleties. We don’t know the right answer yet,” Dr. Rini said. “We hope to sort this out over the next several years.”
“We now have three combination treatments positioned as first-line treatments,” said Robert Motzer, M.D., of Memorial Sloan Kettering Cancer Center, who was a lead investigator on the avelumab–axitinib study. Assuming these new combinations receive FDA approval, he expects that factors such as quality of life, safety, and the proportion of patients who experience complete responses will influence which treatments are used.
Before the advent of drugs like sunitinib, kidney cancer had a poor prognosis, with a median overall survival of less than a year, Dr. Motzer noted. With the use of VEGFR inhibitors, median survival improved to about 30 months.
And now immunotherapies are helping extend survival beyond 3 years, he said.
Treatments will continue to be given in sequence, he explained, as the existing treatments eventually stop working for most patients with advanced kidney cancer and their disease progresses.
In addition to studying different treatment sequences, researchers are also investigating whether they can identify features of tumors, or biomarkers, that can help predict which therapy might work better in different individuals, Dr. Motzer said.
“Ultimately, what’s most important to patients is the impact of these new approaches on long-term survival. How many patients have remissions? Are any patients actually cured of their kidney cancer?” Dr. McDermott said. “It’s going to take some time to figure those things out.”
Some of the new treatments for advanced kidney cancer are also being tested as adjuvant therapy in some patients diagnosed with less advanced disease who can be treated with surgery, he noted, especially those with stage III disease.
The adjuvant trials are currently enrolling patients, Dr. McDermott said, and he encouraged physicians and patients to consider joining the available trials.
Targeted Therapy–Immunotherapy Combinations Effective for Advanced Kidney Cancer
March 19, 2019, by NCI Staff
Results from two large clinical trials are expected to change the initial treatment for many people with newly diagnosed advanced kidney cancer.
In both studies, combination treatments that included a type of immunotherapy called an immune checkpoint inhibitor and the targeted therapy axitinib (Inlyta) led to better outcomes for patients with advanced kidney cancer than treatment with sunitinib (Sutent) alone, the standard of care for first-line therapy.
Results for the two phase 3 trials were reported last month at the American Society of Clinical Oncology Genitourinary Cancers Symposium (GU ASCO) in San Francisco and simultaneously published in the New England Journal of Medicine (NEJM).
The Food and Drug Administration (FDA) has already approved one immunotherapy combination as an initial, or first-line, treatment for people with advanced kidney cancer. And, based on these new data, several experts on the disease said further approvals for these patients are likely to be forthcoming.
“There’s a lot of exciting data. The treatment landscape is changing quickly,” said David McDermott, M.D., chief of medical oncology at Beth Israel Deaconess Medical Center, who has been involved in kidney cancer immunotherapy studies.
Evolving Treatment Strategies for Advanced Renal-Cell Cancer
In the last 12 years, the treatment of metastatic renal-cell cancer “has been revolutionized twice,” wrote Bernard Escudier, M.D., of the Gustave Roussy Cancer Campus in France, in an editorial accompanying the two papers in NEJM.
The first big change occurred more than a decade ago with the advent of targeted therapy. Sunitinib and, later, axitinib and similar drugs were developed that block a protein called the vascular endothelial growth factor receptor (VEGFR), which plays an important role in kidney cancer.
These targeted treatments were shown to be more effective than what was then the first-line treatment, interferon alpha, a treatment that worked only in a small number of patients and had serious side effects.
A second big change came in 2015, Dr. Escudier wrote, when the immune checkpoint inhibitor nivolumab (Opdivo) was shown to be effective in patients with advanced kidney cancer that had progressed after their initial treatment, soon after becoming the standard of care for these patients.
In 2018, FDA approved the combination of nivolumab and ipilimumab (Yervoy), two immune checkpoint inhibitors, as an initial treatment for the disease, after a large clinical trial showed that the approach led to better survival compared with patients treated with sunitinib.
Combining Targeted Therapy and Immunotherapy
The new trials took a different approach, combining the two strategies—a VEGFR inhibitor (axitinib) and an immune checkpoint inhibitor—that have been effective in treating kidney cancer on their own.
The studies used different immunotherapy agents but were otherwise very similar. Both trials enrolled more than 800 patients with previously untreated advanced clear-cell renal-cell carcinoma.
One study, funded primarily by Pfizer, tested the immune checkpoint inhibitor avelumab (Bavencio) in combination with axitinib, and showed that patients treated with the combination lived longer without their disease worsening (progression-free survival) compared with patients treated with sunitinib.
The second study, funded primarily by Merck, tested the immune checkpoint inhibitor pembrolizumab (Keytruda) along with axitinib and showed a significant improvement in how long participants lived overall (overall survival), as well as progression-free survival compared with sunitinib.
Toni Choueiri, M.D., of the Dana-Farber Cancer Institute, a senior author on the avelumab–axitinib study, explained, “We built the combination based on the fact that axitinib works in kidney cancer, and avelumab is in a class of agents that also work on kidney cancer. So you bring together two drugs that work.”
Earlier, smaller studies had shown that axitinib could be combined with either avelumab or pembrolizumab, all at full dose without causing unacceptable levels of toxicity in the liver. In contrast, combining sunitinib with an immune checkpoint inhibitor caused severe side effects, Dr. Choueiri said.
Axitinib targets VEGFR more specifically than sunitinib does, explained Brian Rini, M.D., of the Cleveland Clinic, a lead investigator on the pembrolizumab–axitinib study. “Axitinib is more potent and better tolerated, and made a better combination partner,” Dr. Rini said.
But some of “the most impressive data to date” for treating advanced kidney cancer are from the pembrolizumab–axitinib study, Dr. McDermott said.
The combination of pembrolizumab and axitinib “broadly out-performed sunitinib in all key [patient] groups,” said study investigator Thomas Powles, M.D., of the Barts Cancer Institute in London, in his presentation of the study results at the ASCO meeting. At a median follow-up of nearly 13 months, approximately 90% of patients treated with pembrolizumab and axitinib were still alive, compared with 78% of patients treated with sunitinib.
In the trial testing avelumab in combination with axitinib, patients treated with the drug combination had longer median progression-free survival (13.8 months versus 8.4 months) and were more likely to have their tumors shrink (objective response) compared with patients treated with sunitinib. At the time of publication, the patient follow-up was not long enough to determine whether there is an improvement in overall survival.
“This year we will assess overall survival,” Dr. Choueiri said.
Follow-up of patients in both studies will continue to monitor survival and long-term side effects, investigators from both trials said. Rates of side effects were high in all treatment groups in both trials, with high blood pressure and diarrhea being among the
most common side effects.
The Shifting Treatment Landscape for Kidney Cancer
Combination treatments have “essentially been proven” to be superior to VEGFR inhibition alone as first-line therapy, Dr. McDermott said. Combination treatments have clear benefits, although they are more costly and cause more side effects, he added.
As for which combination treatment will be the best for which patients, that’s still unclear, Dr. Rini said. “There are subtleties. We don’t know the right answer yet,” Dr. Rini said. “We hope to sort this out over the next several years.”
“We now have three combination treatments positioned as first-line treatments,” said Robert Motzer, M.D., of Memorial Sloan Kettering Cancer Center, who was a lead investigator on the avelumab–axitinib study. Assuming these new combinations receive FDA approval, he expects that factors such as quality of life, safety, and the proportion of patients who experience complete responses will influence which treatments are used.
Before the advent of drugs like sunitinib, kidney cancer had a poor prognosis, with a median overall survival of less than a year, Dr. Motzer noted. With the use of VEGFR inhibitors, median survival improved to about 30 months.
And now immunotherapies are helping extend survival beyond 3 years, he said.
Treatments will continue to be given in sequence, he explained, as the existing treatments eventually stop working for most patients with advanced kidney cancer and their disease progresses.
In addition to studying different treatment sequences, researchers are also investigating whether they can identify features of tumors, or biomarkers, that can help predict which therapy might work better in different individuals, Dr. Motzer said.
“Ultimately, what’s most important to patients is the impact of these new approaches on long-term survival. How many patients have remissions? Are any patients actually cured of their kidney cancer?” Dr. McDermott said. “It’s going to take some time to figure those things out.”
Some of the new treatments for advanced kidney cancer are also being tested as adjuvant therapy in some patients diagnosed with less advanced disease who can be treated with surgery, he noted, especially those with stage III disease.
The adjuvant trials are currently enrolling patients, Dr. McDermott said, and he encouraged physicians and patients to consider joining the available trials.