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Pembrolizumab (Keytruda): CADTH Reimbursement Review: Therapeutic area: Advanced endometrial cancer [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2023 Apr.
The Colorectal Cancer Resource & Action Network (herein ‘CCRAN’) led a collective patient input submission on Pembrolizumab monotherapy and Pembrolizumab in combination with Lenvatinib for the treatment of advanced endometrial cancer. The following patient advocacy groups thoughtfully collaborated with CCRAN to provide meaningful and compelling patient input:
All patient groups are registered with CADTH.
Please note: CCRAN is a national not for profit patient advocacy group championing the health and wellbeing of Canadians touched by colorectal cancer and those at risk of developing the disease. CCRAN has recently expanded its patient-focused mandate to serve a population of patients with cancer outside of the colorectal cancer space by providing HTA patient and clinician input submissions within the oncology space for:
To ensure the advanced endometrial cancer patient perspective was captured for this critically important therapeutic under review, CCRAN employed a multi-faceted outreach approach. On November 11, 2021, we reached out to 12 Canadian clinicians via email who treat advanced endometrial cancer patients requesting assistance identifying patients who had/have experience with Pembrolizumab + Lenvatinib who would be willing to participate in a telephone interview to share that experience for an HTA patient input submission being made to two expert committees in Canada. That same email was followed up on November 28th, 2021. On December 6th, 2021, the President (Dr. Helen MacKay) of The Society of Gynecologic Oncology of Canada (‘GOC’) was respectfully contacted with the same request. The GOC kindly sent a mass email authored by the GOC President on CCRAN’s behalf to the members of the GOC on December 9th, 2021, requesting assistance with patient recruitment.
Additionally, a connection was made between CCRAN and the Mission Coordinator from the Canadian Cancer Society (CCS) on November 29, 2021, ensuring CCS support the inclusion of the endometrial cancer patient’s values and preferences in this submission through a recent online survey they conducted regarding the endometrial cancer patient’s:
The online survey was administered from October 22nd to November 3rd, 2021, wherein 22 survey respondents provided input.
Best Description of Respondents.
Province or Territory Respondents Reside In.
Age of Respondents.
The CCS survey findings will be referenced throughout this submission for they reflect the perspectives of the endometrial cancer patient population. CCS also sent out mass emails on behalf of CCRAN requesting advanced endometrial cancer patients who have experience with the therapy under review contact CCRAN for a telephone interview to kindly share that experience. Emails were also shared by the CCS with Cancer Connection Forum and with McGill University Health Center’s Gynecological Unit. Additional outreach efforts were made on behalf of CCRAN to the following American and European based organizations with similar requests:
Force: www.facingourrisk.org; Cancer Care: www.cancercare.org; ESGO https://engage.esgo.org
One additional outreach effort was made to the Canadian Cancer Survivor Network (CCSN) on December 5, 2021, who employed an online survey as well, resulting in one endometrial cancer patient having experience with the therapy under review.
It was the clinician and GOC outreach efforts that resulted in 1 caregiver and 3 advanced endometrial cancer patient telephone interviews. Telephone interviews were conducted by CCRAN between December 1st and December 14th, 2021, inclusive, with each patient providing firsthand compelling, relevant and high-quality input regarding their:
The mean age of the patients was 62 years, and the median age was 64 years at the time of their diagnosis. The qualitative data from the interviews is summarized and represented entirely, which will serve, for the most part, as the basis for this qualitative submission, in addition to the survey findings furnished by CCS, and the one survey result supplied by CCSN.
Endometrial cancer is the most common gynecological malignancy in Canada and our interviewed patients were surprised to learn from their treating oncologists that its incidence is increasing. Sadly, no specific screening is recommended in the general population which may account, in part, for the advanced disease case counts, which are associated with a poor prognosis, primarily because patients with advanced endometrial carcinoma have limited treatment options.
Most women with endometrial cancer will present with abnormal bleeding, irregular cycles and/or excessive bleeding in the premenopausal female, or any bleeding in the post-menopausal setting. In the advanced disease setting, women may complain of pelvic and abdominal discomfort, bloating, or presence of a mass, gastrointestinal or genitourinary symptoms, or constitutional symptoms. According to the qualitative data, all four patients had been experiencing incessant vaginal bleeding for a period of at least 6 months to >2 years. Patient B reported having experienced a mucus-type vaginal discharge accompanied by significant abdominal discomfort in addition to her vaginal bleeding. Three of the four patients (Patients A, B, and D) expressed significant frustration and profound disappointment over their ongoing symptoms whose cause could not be identified for quite some time, despite repeated diagnostics, which they believe contributed to their disease progression and diagnosis of advanced stage disease.
“I had been symptomatic for years, whose cause couldn’t be understood or identified. I just kept bleeding and bleeding. The ultrasounds couldn’t pick anything up and then I had a CT scan that sort of picked up something, so I went on to have a D&C which picked up my cancer…I was then scheduled for my surgery. And I have to tell you that 10 minutes before I went into my surgery, I found out that I had metastatic disease to my lungs. It was so shocking and disappointing. How awful for me.” — Patient D
The Canadian Cancer Society (CCS) Survey findings (n=22) clearly demonstrated the impact of the disease on the patient’s day to day activities and ultimately their quality of life. Q3 of the survey asked, “How much of an impact do symptoms associated with endometrial cancer have on your day-to-day activities and quality of life?” Patients diagnosed with endometrial cancer were asked to select all that apply from a list of tasks. Those tasks scoring highest in the moderate to significant impact range included the ability to:
Impact Symptoms Associated With Endometrial Cancer Have on Day-to-Day Activities and Quality of Life.
The CCSN survey respondent also expressed concerns regarding her day-to-day living. She identified “living with uncertainty, feeling isolated or lonely” and that she experienced “diarrhea, occasional interstitial cystitis, and herpes outbreaks” which compromised her quality of life.
Interviewed Patients B and D both shared that they had cancer induced symptoms with which they had struggled. Patient B had endured pelvic pain and constipation; while Patient D was fraught with fatigue, nausea, and a lack of appetite (Q17).
The four interviewed patients articulately and vividly described the toll a diagnosis of advanced endometrial cancer plays on the caregiver. Th diagnosis can be equally frightening for the caregiver, who is typically the spouse, but can be anyone – a family member, friend or loved one. The caregiver may take on many roles in the course of the patient’s journey. They will assume the role of medical translator, information specialist, housekeeper/meal preparation, financial advisor, psychosocial expert, and so much more. Quite often the caregiver’s function is overshadowed or under- valued; in large part because the focus is typically on the patient, thus discounting the essential role played and meaningful contribution delivered by the caregiver. Our interviewed patients painfully described the stress, and debilitating anxiety a caregiver undergoes once a diagnosis of advanced endometrial cancer is delivered to the family. They explain (Q22):
“Yes, it was life-altering. We have been through a major trauma, even to this day, it still affects us. The impact is lifelong. Both my sister and I were quite young. She and I would take turns taking my mom to her appointments. We would do research …. We struggled with the side effects of the treatments, learning how to give her injections every day for her thrombosis. …dreadful disease.” — Caregiver A
“My husband has always been there but emotionally; it has been very draining and stressful for him. He had to become Dr. Google overnight. He came to all my appointments and to the 6 cycles of chemo and had to deal with all the chemo side effects which were brutal. Then covid kicked in and he couldn’t come with me so that was so very stressful for him. So, he sat in his car and waited for me the whole time. He was there the whole time for me, including during surgery. And he has his own health issues…” — Patient B
“My husband was there taking care of me, doing housework, cooking, I guess just taking on the bulk of responsibilities because I couldn’t do it. But then in 2019, he had a stroke and now he is different and compromised, it is difficult for him. He had to do rehabilitation because of his stroke. He really cannot help me. I had to make arrangements for him and for me. For example, who will go first, him or me? It is a terrible situation. His stroke may not have been caused by my diagnosis, but my diagnosis may have impacted his health to the point where it could have contributed to his poor health…. Cancer does atrocious things to not only the patient but to their family members.” — Patient D
Patients with advanced endometrial carcinoma have limited treatment options. If diagnosed with an early stage of the disease, patients will undergo surgery to remove the uterus (and perhaps the cervix), fallopian tubes and regional lymph nodes. Radiation therapy may also be indicated to kill cancer cells in addition to hormonal therapy to block cancer growth. Carboplatin in combination with paclitaxel are standard chemotherapy treatments indicated for endometrial cancer in both the adjuvant setting and first line treatment of metastatic endometrial cancer. These therapies, particularly the latter, are associated with treatment induced toxicities that compromise patients’ quality of life and fail to extend patients’ longevity in a meaningful way.
The CCS survey findings (Q8) captured the impact of treatment-induced toxicities as reported below in the figure. Previously administered treatments included surgery, chemotherapy (Caelyx, Carbotaxol) and hormonal therapy (Anastrozole). Surveyed patients selected “changes in libido or sexual function” as the most significant side effect resulting from their previous treatment(s) with 10 responses appearing in the moderate to significant impact range. Fatigue (9), constipation (6), and peripheral neuropathy (5) followed, as highlighted in the table.
Impact of Treatment-Induced Toxicities.
CCS captured patient input through firsthand testimonials as well which described the harsh and debilitating side effects these patients endured as they underwent standard of care treatments indicated for the management of their advanced endometrial cancer. These testimonials also highlight the overall lack of efficacy associated with these standard of care therapies that compromised their everyday quality of life. Appearing below is one of the testimonials CCS secured outside of the Survey:
“The first line of chemotherapy gave me very bad side effects, pain and complications. They gave me first and second line chemotherapy sessions, both had very bad side effects and were not effective.…. At that point, they gave me radiation to shrink the tumour, and yet that was only for one small tumour that I had…. My abdominal pain became worse and worse. The pain medications were not effective.” CCS Patient Testimonial
Interviewed patients provided thoughtful input regarding their treatment journeys. Caregiver A summarized her mother’s experience as quite ghastly. Her mother underwent surgical resection and then received radiation therapy which she tolerated quite well, and it controlled her cancer for approximately 3.5 years but spinal and bone metastases eventually ensued. She was prescribed Nexavar to which there was no response. Her mother was then prescribed second line Carbotaxol but could only endure 2 cycles due to “horrible side effects” that were debilitating and unmanageable. Her mother then succumbed to the disease.
Patient B underwent surgical resection for her cancer but shortly after her surgery (3 months) she was diagnosed with a mass that was strangulating her left ureter as well as metastases to her spleen, liver and peritoneum. She was prescribed 6 cycles of Carbotaxol to which there was little response. Her left kidney failed due to hydronephrosis. She was then recommended the therapy under review (Pembrolizumab + Lenvatinib).
After undergoing surgical resection for her cancer, Patient C endured 6 toxic cycles of Carbotaxol and 3 treatments of brachytherapy for any remnant microscopic disease. Sadly, she was diagnosed with a recurrence in her peritoneum and spine for which she was prescribed more Carbotaxol (6 cycles). She initially experienced a partial response to the Carbotaxol and eventually progression. She was then prescribed hormonal therapy, Letrazole in combination with Vitamin D but that too showed progressive disease. She then started Doxorubicin (6 cycles) but had to stop due to diminished quality of life and eventually progressive disease developed and was recommended Pembrolizumab + Lenvatinib).
Patient D was diagnosed with metastatic disease (lungs) as she was being wheeled into surgery. She was prescribed Carbotaxol. She could only endure one cycle of the carboplatin due to extreme neuropathy. She then continued on with the paclitaxel only, which regressed the lung metastases but was ineffective against the abdominal disease which was discovered post op. She was recommended Pembrolizumab monotherapy.
Carbotaxol was accessed by all four of our interviewed patients (Patients A, B, C and D) as a treatment option for women with advanced endometrial cancer. All four patients reported debilitating side effects while being on Carbotaxol despite having spent a relatively short period of time on the drug therapy (<2 months, 4 months, 6 months, 5 months respectively), and sadly none of the patients reported having benefited from the treatment. Patient reported side effects from Carbotaxol therapy included: neuropathy, fatigue, nausea, lack of energy, headaches, hypothermia, cramping in extremities, abdominal pain, hair loss and diarrhea. Patients were disheartened to learn of the lack of response and their quality of life was significantly impacted to the point where they were unable to function because they were physically unwell and debilitated. They were quite emphatic about their experience with Carbotaxol, despite the fact that it was short lived. In their words (Q8A-C):
“…her life started to deteriorate. So, when she started Nexavar, her quality of life got worse. She could no longer socialize or travel. And Carbotaxol was the worst of them all. Horrible side effects. Her outlook even became negative. She even stopped working. And it was so difficult to watch from a caregiver’s perspective.” — Caregiver A
“I had typical side effects while I was on the Carbotaxol. I had hair loss…. I had absolutely no energy. The coldness and chills were horrible. I couldn’t do any housework or shopping. I had to have everything delivered because that was very challenging for me due to fatigue and exhaustion. My energy level was so low, and I was so weak. I tried to stock my house with products and food. My husband did the cooking and cleaning. Thank goodness. How do single women get through this? I can’t imagine.” — Patient B
“When I was on the Carbotaxol, my quality of life was really not so good, actually, it was pretty terrible. It was because of the pain in my hands. They were like electroshock waves were going through them. They were also numb at the same time. It was hard to explain. I hated it so much. I still have the pain to this day. The doxorubicin was not painful, but my heart is not the same anymore. I am at a lower level today and as a result I have to be careful with activity like running, walking etc…. My heart is 70% at its pumping capacity now because of doxorubicin. Isn’t that awful?” — Patient C
“I was totally dependent on my husband while on Carbotaxol. He would have to give me showers, dry my hair, I couldn’t dry myself after a shower, he had to help me dress myself, I couldn’t cook, I couldn’t clean the house, I was a total clean freak and I had to abandon that. I couldn’t do anything around the house. I couldn’t leave the house for weeks and weeks because I had no energy due to the chemo. I couldn’t do grocery shopping or any type of shopping. I wasn’t engaged in life at all. There was no socializing for me at all. I couldn’t even go to church or see my kids and grandkids who I cherished so much. The side effects of chemo were so brutal. I had nausea, fatigue, no energy at all, I had headaches which bound me to bed, I was useless. I slept a lot. All these were so severe 80% of the time. They had to take me off the carboplatin because of the neuropathy. What sort of life is this to lead?” — Patient D
Q10 of the CCS survey asked, “What improvements would you like to see in new treatments that are not achieved in currently available treatments?” Open ended survey replies included: fewer side effects such as skin issues, fatigue, bladder control, stamina, vaginal bleeding after intercourse, vaginal dryness, hair loss, pain, concentration problems (chemotherapy fog) and arthritis. Respondents also indicated they would like to see more drug affordability as the cancer journey can become quite expensive while undergoing treatment, as usual everyday activities may become interrupted, requiring additional expenditures to help cover or assume those activities.
All interviewed patients provided their perspective on the improvements (Q25) they would wish to see associated with a new drug therapy – improvements they believe are currently not available with standard of care therapies for the management of advanced endometrial cancer. They passionately expressed the following: a desire to access a therapy that would promote good quality of life while effectively regressing their disease.
“I would like to see an extension in life and of course a reduction in side effects that will permit a patient from living their life with some degree of normalcy or a good degree of quality of life.” — Caregiver A
“Treatments should have better side effects for everyone.” — Patient C
These interviewed patients focused heavily on being able to access a drug therapy that could be free of debilitating side effects, allowing them the ability to live their lives with some degree of normalcy. One patient (Patient B) also emphasized the need to access therapies that can be easily administered, in the comfort of their own home: an oral therapy that would minimize visits to the cancer centre. In patients’ own words:
“I would say that all therapies should come in a pill form, have no side effects or minimal side effects, and it should shrink the disease big time!” — Patient B
“I would probably like to see a better quality of life – so I guess no side effects, because of what I went through. A better drug on the market because of the damage I underwent. It was horrible what I went through. Cancer is not so easy so it would be helpful to go through it with a drug that provides a good quality of life.” — Patient D
Furthermore, the three interviewed patients (Patients B, C and D) maintain the therapy under review currently possesses these desired improvements and were extremely grateful to have been able to access this therapy (Q26). According to their explicit and detailed input, it has prolonged their life significantly with minimal to no side effects, promoting excellent quality of life. Their lives have been truly ameliorated, such that they have been able to resume normal daily activities, spend quality time with friends and family (pandemic notwithstanding), permitting them the freedom to “living life again”. In their own words, patients provided the following input regarding the current therapy (Pembrolizumab monotherapy and Pembrolizumab + Lenvatinib) possessing the desired improvements:
“Yes, I do! Look at my results! My disease was so stubborn, but this therapy has reduced my disease considerably and the side effects have been so great and so very minimal for me. My quality of life has been excellent.” — Patient B
“Yes! it’s fantastic, I do not feel any side effects at all. I would say it has been constructive being on this immunotherapy vs having been on previous therapies like chemo which I would consider as destructive.” — Patient C
“Yes, I certainly do. It has given me all of that and so much more because I am myself again. I have my life back. I believe that says it all.” — Patient D
The treatment-related experiences were captured for three interviewed Canadian patients who are currently undergoing the therapy under review. One additional patient provided input regarding her experience with the therapy through the CCSN online survey. In total, four patients provided compelling input (Patient B and C provided input regarding Pembrolizumab + Lenvatinib; Patient D provided input regarding Pembrolizumab monotherapy; and the CCSN patient provided input regarding Pembrolizumab + Lenvatinib), all of whom underscored the dire need to improve therapeutics for the management of advanced endometrial cancer because patients diagnosed with recurrent or metastatic endometrial cancer have limited treatment options. And the options that are available to them are not only short lived but riddled with debilitating side effects. The following four patients were diagnosed with metastatic, chemotherapy resistant endometrial cancers treated with pembrolizumab + Lenvatinib who, having achieved long term durable responses, wished to share their experiences for the purposes of informing your deliberative processes:
Patient B was a 51-year-old female who underwent surgical resection of her endometrial cancer. Three months post op, she was diagnosed with a mass that was strangulating her left ureter as well as metastases to her spleen, liver and peritoneum. She was prescribed 6 cycles of Carbotaxol to which there was little response. Her left kidney failed due to hydronephrosis. She was then recommended Pembrolizumab in combination with Lenvatinib in October 2019 as part of a clinical study in second line therapy.
Patient C was a 64-year-old female who underwent surgical resection, endured 6 toxic cycles of Carbotaxol and 3 treatments of brachytherapy. She was diagnosed with recurrent disease in her peritoneum and spine for which she was prescribed first line Carbotaxol (6 cycles). Progression ensued. Hormonal therapy (Letrazole) + Vitamin D was then prescribed as part of second line therapy to which there was no response. Third line therapy followed consisting of Doxorubicin (6 cycles) to which she responded poorly and experienced diminished quality of life. In August 2021, the patient accessed Pembrolizumab + Lenvatinib through a private pay plan as part of fourth line therapy.
Patient D is a 69-year-old female who learned of her metastatic disease to her lungs as she was being wheeled into surgery. She was prescribed first line Carbotaxol post op. She could only endure one cycle of the carboplatin due to significant neuropathy but did continue with the paclitaxel portion, which regressed the lung metastases but was ineffective against the abdominal disease, which appeared while on the paclitaxel. She was then recommended Pembrolizumab monotherapy as part of second line and began treatment in June 2021, accessed through her husband’s private insurance plan.
The CCSN patient accessed standard of care therapies such as Carbotaxol as well as complementary therapies and alternative medicines that were somewhat effective but due to progressive disease, did go on to access Pembrolizumab + Lenvatinib through a clinical trial. The Pembrolizumab + Lenvatinib provided tumour shrinkage and slowed progression of disease according to the patient input. It did, however, cause undesirable treatment induced side effects such as diarrhea and herpes outbreaks.
The three interviewed patients accessed the therapy under review with great anticipation and hope because they had either exhausted standard of care therapies for the management of their cancer (Patient C) or had been recommended to enroll in a clinical trial that could prove helpful in the treatment of their cancer (Patient B) or could molecularly target their particular cancer: MSI-High Cancer (Patient D). Two of the three interviewed patients (Patients C, D) experienced no side effects whatsoever from their Pembrolizumab + Lenvatinib and Pembrolizumab monotherapy treatments respectively (Q15A).
“No, not at all. It has been amazing. I am a little tired because of the previous therapies I was on, but no, no side effects at all, whatsoever.” — Patient C
“Nope, no side effects whatsoever.” — Patient D
Patient B experienced two treatment-induced side effects: diarrhea and mild fatigue, both of which are well managed and easily controlled. She was prescribed loperamide to control the diarrhea and Synthroid for the fatigue, both of which are no longer issues.
“The main side effect I have experienced is irritable bowel syndrome (diarrhea) for which I was prescribed loperamide. And I had some fatigue at the end of the treatment, in August so they put me on Synthroid. The diarrhea was mild because if I watch what I eat, it is ok. I get to manage it very well. And the fatigue is mild as well. That’s pretty much it.” — Patient B
And the CCSN patient reported the following treatment-induced side effects: fatigue, diarrhea, and urinary tract infection. She does report there has been tumour shrinkage and that the therapy has “slowed progression of disease”. Interviewed patients were asked to rate their quality of life while on the therapy under review (Q16). All three patients provided high scores: 9, 8, and 10, generating an average score of 9, and two patients provided comments with their scores:
“My life has definitely been better since being on this therapy both from a quality-of-life perspective and from a survival perspective.” — Patient B
“I feel so good while on this therapy. I am as I am right now, all the time.” — Patient D
All three interviewed patients maintain that Pembrolizumab + Lenvatinib or Pembrolizumab monotherapy has delivered a remarkable response wherein their disease has regressed significantly in addition to having provided them with an excellent quality of life (Q19). The objective findings from diagnostics such as imaging (CT – except for Patient C) and labs support their improved overall well-being. Clinically, they feel better! In the patients’ own words:
“First, I felt better. I had no more cancer symptoms. I could go to the bathroom. I had no more constipation, and I had no more pain in my pelvis. And the tingling resolved. And the CT scan showed that I was responding to the therapy. They were taking measurements every time I had a CT scan. My cancer shrank by 70%! and now there is so much scar tissue. It is pretty much dead in there. I am so lucky to have been on this therapy. It has been so wonderful for me.” — Patient B
“I had 2 CT scans so far that confirmed response. The first CT scan showed lots of improvement in all tumours including my belly. The second one showed more improvement in all tumours too. I also feel so well. That’s a sign that the treatment is working. I have no more cancer symptoms. I could go on taking this therapy with no side effects forever.” — Patient D
All three interviewed patients cited how much easier the therapy under review was to use when compared to previously administered therapies, resulting in a superior quality of life (Q21). For patients who accessed Pembrolizumab + Lenvatinib: patients appreciated the opportunity to access an oral therapy (Lenvatinib) which is easily administered in the comfort of their own homes, thereby avoiding a long and grueling stay and infusion time at the cancer centre.
Patients also appreciated the short infusion time associated with Pembrolizumab (30-45 minutes), administered every 3 weeks, which is unlike the infusion times associated with previously administered standard of care therapies for advanced endometrial cancer (Carbotaxol and Doxorubicin).
“Yes, it has. When I was on the Carbotaxol, I used to have to sit in an infusion chair for 8 hours a day at the hospital and I have no more veins because of it. I now require a portacath because of that now. What a horrible therapy. But now, because of this immunotherapy, it is done in a 45-minute infusion, and I have no side effects. And the other half of the therapy I get to take at home. And the other beauty of it is, there is no Decadron anymore, woohoo! So no more discomfort. I am so happy about that. I love this treatment. It is wonderful and I have no pain. It is fantastic to take. And I get an oral therapy at home. What more can you ask for as a cancer patient?”
Two of the three interviewed patients (B and D) struggled with cancer induced symptoms prior to starting the therapy under review and in each case the therapy provided significant resolution of those symptoms. In Patient B’s case, her pelvic and abdominal disease regressed after starting Pembrolizumab + Lenvatinib which in turn resolved her pelvic pain and constipation. Patient D had been experiencing fatigue, nausea, lethargy and lack of appetite, due entirely to the disease in her abdomen but these symptoms completely resolved after commencing Pembrolizumab monotherapy. The therapy has regressed the disease in both these patients to the point where symptoms have completely ameliorated (Q17). Patients expressed how grateful they were to be rid of those cancer induced symptoms:
“…. I don’t have any of those symptoms anymore. The therapy shrank my cancer and took all those symptoms away.” — Patient B
“Pembrolizumab helped to resolve all of them. It was a miracle. I don’t have any of them anymore. Apparently, a lot of those symptoms were because of the disease in my belly. But the disease in my belly has shrunk so much, it is not giving me problems anymore or symptoms. They are completely gone.” — Patient D
Interviewed patients have been undergoing the therapy under review for, what is in some cases, an extended period of time, reflective of sustained and durable responses: 26 months, 4 months, 5 months. Efficacy was radiographically and clinically confirmed in each patient’s case (save Patient C who was scheduled to undergo imaging within a few weeks of their telephone interview, but the patient was quite emphatic that based on how they were feeling clinically and their labs, response was imminent and would correlate with CT scan findings (Q19).
Patients B, C and D were quite expressive and became emotional when describing what impact the therapy has had on their lives and what they have managed to accomplish or fulfill. They expressed profound disappointment with having accessed previous therapies that failed to successfully treat their cancer and caused indescribable pain, suffering and anguish, enduring unimaginable and debilitating side effects. But the therapy under review has been and continues to be their lifeline, a “miracle” drug (Patient D), a “God-sent” (Patient C), without which they would not be alive today. They credit their longevity and ability to function at an almost normal level entirely to Pembrolizumab + Lenvatinib or Pembrolizumab monotherapy. Patients were able to resume what most would consider to be a normal lifestyle while undergoing therapy, but wished to note that this was quite extraordinary for a cancer patient based on their experience with previously administered therapies. Interviewed patients reported significant improvements in health status while undergoing the therapy under review (both Pembrolizumab + Lenvatinib and Pembrolizumab monotherapy) with respect to physical function and overall quality of life. They were able to resume responsibilities such as grocery shopping, housework, cooking, baking, caring for their loved ones – responsibilities most healthy Canadians take for granted (Q24). But Patient C no longer takes these simple chores for granted in the setting of a cancer diagnosis. She is grateful to be able to perform them while actively undergoing cancer therapy. Patients were also able to fulfill and accomplish a great deal while on the therapy. They mention being able to travel, resume their studies, spend quality time with family and cherished friends, complete their sailing certification, rejoin the YMCA to rebuild muscle mass, engage in social media, and so much more. Patients can not only function, but they can thrive.
This life altering therapy has been repeatedly referred to as a “gift” and a “miracle” or that which has provided patients with great “hope” because it has offered them significant life extending properties while improving the patient’s quality of life. Additionally, it is worth noting that adverse events resulting in permanent discontinuation of the drug occurred in none of the patients; dosage interruptions due to an adverse reaction occurred in none of the patients; one patient (C) experienced a dose reduction (14mg to 10mg/day) in the Lenvatinib in the first few days of starting therapy due to headaches but has never experienced any issues since (Q20). Patients were overcome with gratitude and emotion throughout the interviews when speaking of their experience with the therapy under review:
“Do you really want an answer? (volume increased 5x). 1000% of course, I am so grateful for this therapy. Of course, of course, of course. I couldn’t afford to pay for this on my own, so I am so terribly appreciative of this. This therapy is my hope for a great extension in life. It is my way of continuing to live. Is it going to change for me? Will I be able to accept it for free in the future? I am so scared I might run out of luck in that respect and be forced to pay for it which is why I am participating today. I pray that I will be able to accept this therapy for free and that others who qualify will be able to accept it for free as well so they can benefit like me.” Patient C
“If I had not accessed this therapy, my life would have spiraled out of control and inevitably, to death. I have been able to travel, take an interest in my studies and my loving family again. Nothing is more important than family. I have nephews who have moved into the city who are spending Christmas eve with us, and I am looking forward to spending time with them which is so special to me and important to me. I have 2 nieces and 2 nephews in Ontario who I am seeing that I get to see because this therapy is making it possible to do so. These are special times because I am well enough to do it – all because of the therapy. These are not remarkable events, but they are nevertheless remarkable to me.” Patient B
Both mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) have been proposed as predictive biomarkers of response to the immune checkpoint inhibitor Pembrolizumab. Approximately 16% of patients diagnosed with recurrent endometrial cancer have tumours with high levels of MSI-H and dMMR (jco.19.02627 (1).pdf) and these patients could benefit from Pembrolizumab monotherapy. Patients need to provide a tissue sample for biomarker analysis (that can be done through IHC or PCR) to help guide treatment. Our interviewed patients were not aware of any specific testing requirements to help determine their biomarker status that would identify them from potentially benefiting from Pembrolizumab monotherapy (Q11A). They were, however, aware of a myriad of testing they had to undergo, to which they happily subjected themselves because they had either exhausted therapeutic options or progressed on standard of care therapies.
“I don’t really know, and I didn’t really ask. All I know is that my tissue went to a tissue bank for testing and my oncologist spoke to me about it.” — Patient B
None of our interviewed patients incurred any out-of-pocket expenses for any diagnostic testing they required to qualify for their therapy (Q11D). Based on previous submissions made by CCRAN, patients’ MSI/MMR status could be determined through IHC testing at their local treatment centre and patients are typically grateful to access the test.
For those who qualify for the immunotherapy based on the identification of a unique biomarker, patients may be able to experience a life prolonging therapy with minimal to no side effects, allowing them to resume their day-to-day activities. For patients whose endometrial tumours are identified to be microsatellite stable (MSS) and mismatch repair proficient (pMMR), they too are able to avail themselves of a life-prolonging therapy that includes pembrolizumab in combination with lenvatinib based on patient input. The combination therapy, according to our interviewed patients (B and C, and CCSN patient), has demonstrated great efficacy in the treatment of their recurrent/metastatic disease. Upfront testing will identify the patients who qualify for monotherapy vs combination therapy and will ultimately change the treatment paradigm and guide treatment decisions. The result, according to patient input, will be improved quality of life due to fewer treatment induced toxicities, disease regression, an oral therapy permitting at home use, and reduced infusion time. For patients who are identified with the unique biomarker (MSI-H/dMMR), the therapy delivers on the promise of precision medicine guiding treatment decisions for advanced endometrial cancer.
The standard of care for patients with advanced or recurrent endometrial cancer is multiagent systemic chemotherapy, which includes Carbotaxol in the first line setting. In addition to being quite toxic, this combination therapy has, according to our patient input, low response rates which creates an urgent, unmet need to provide treatment options that yield better outcomes for this patient population: outcomes that include fewer side effects contributing to an improved quality of life, an extension in progression free survival and overall survival.
The patients who received Pembrolizumab monotherapy or Pembrolizumab + Lenvatinib reported significant improvements in health status with respect to physical function and overall quality of life. According to patients, the therapy has fewer side effects compared to previously administered therapies. Patients expressed their profound gratitude for having been able to access the therapy under review because for the most part, it has delivered a robust, durable, safe and effective response compared to previously accessed therapies with a substantially favorable toxicity profile. This was repeatedly stressed throughout the captured data. They also appreciated the shorter infusion time of the therapy and the convenient use of an oral therapy, easily administered at home. Patients stated they wish to continue to avail themselves of the therapy and wish same for others who qualify.
The use of Pembrolizumab monotherapy in the MSI-H/dMMR patient and Pembrolizumab + Lenvatinib in the MSS/pMMR patients demonstrated a level of benefit unlike any other previously accessed treatment. These patients were permitted to resume a “normal, active lifestyle” which patients’ credit entirely to the therapy. They were once again engaged in life in a meaningful way – contributing members of society, their families and their communities. The use of the therapy under review helps to address the urgent, unmet need that currently exists in the management of metastatic/recurrent endometrial cancer.
If publicly funded:
Funding these therapies in the appropriate settings (based on the identification of a unique biomarker), aligns well with the patient perspectives captured within this submission. Interviewed patients and their caregivers strongly supported the need for a positive funding recommendation be issued for Pembrolizumab monotherapy and Pembrolizumab + Lenvatinib for the treatment of MSI-H/dMMR and MSS/pMMR advanced endometrial cancer. The interviewed advanced endometrial patient population whose voice was captured and submitted herein underscores that the therapy under review aligns well with the identified need for a new, effective, quickly and easily administered, less toxic treatment option that is capable of maintaining a high quality of life. Survey data provided by CCS for this submission further underscores that patients and caregivers are asking for treatments that are more effective, but with non- debilitating side effects so they can lead a better quality of life, with the longest remission possible and fewer visits to the clinic.
To maintain the objectivity and credibility of the CADTH CDR and pCODR programs, all patients in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission?
No.
Did you receive help from outside your patient group to collect or analyze data used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for the Colorectal Cancer Resource & Action Network.
To maintain the objectivity and credibility of the CADTH CDR and pCODR programs, all patients in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission?
No.
Did you receive help from outside your patient group to collect or analyze data used in this submission?
The network of the Division of Gynecologic Oncology at McGill University Health Center provided the testimonials which were written by patients. One nurse assisted a caregiver by writing down his verbal testimonial as indicated in the testimonial itself. They also shared our survey directly with patients.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for the Canadian Cancer Society.
To maintain the objectivity and credibility of the CADTH CDR and pCODR programs, all patients in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This Patient Group Conflict of Interest Declaration is required for participation. Declarations made do not negate or preclude the use of the patient group input. CADTH may contact your group with further questions, as needed.
Did you receive help from outside your patient group to complete this submission?
No.
Did you receive help from outside your patient group to collect or analyze data used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review.
Financial Disclosures for the Canadian Cancer Survivor Network.
OH-CCO’s Drug Advisory Committees provide timely evidence-based clinical and health system guidance on drug- related issues in support of CCO’s mandate, including the Provincial Drug Reimbursement Programs (PDRP) and the Systemic Treatment Program.
This input was jointly discussed with the listed DAC members.
Pembrolizumab monotherapy: This therapy would be for individuals with mismatch repair deficiency (MMRd)/MSI-H endometrial cancer (EC) that has progressed after chemotherapy (after adjuvant chemotherapy in advanced stage or after chemotherapy for recurrent disease). Currently there are no agents that have specific approval for treatment of recurrent/progressive EC. At time of recurrence there are limited chemotherapy options and trial of carboplatin/taxol retreatment or Adriamycin at progression is current standard of care. The response to these limited chemotherapy options is poor. There are limited options with clinical trial enrolment for patients with advanced EC. There is currently no evidence for another line of therapy and therefore best supportive care would be an option. There are no special access programs for this population of patients. There is a limited subset of patients that are ER/PR positive that would be eligible for hormonal therapy (ex. Letrozole). The hormonal therapy available has limited low-level data and not Health Canada approved indication.
Lenvatinib in combination with Pembrolizumab: Currently there are no agents that have specific approval for treatment of recurrent/progressive EC. At time of recurrence there are limited chemotherapy options and trial of carboplatin/taxol retreatment or Adriamycin at progression is current standard of care. The response to these limited chemotherapy options is poor. There are limited options with clinical trial enrolment for patients with advanced EC. There is currently no evidence for another line of therapy and therefore best supportive care would be an option. There are no special access programs for this population of patients. There are a limited subset of patients that are ER/PR positive that would be eligible for hormonal therapy (ex. Letrozole). The hormonal therapy available has limited low-level data and not Health Canada approved indication.
Pembrolizumab monotherapy: The most important goals would be prolonged life, delay disease progression, symptomatic relief, partial response, full response, improved health-related quality or life, and decreased treatment toxicity.
Lenvatinib in combination with Pembrolizumab: The most important goals would be prolonged life, delay disease progression, symptomatic relief, partial response, full response, and improved health-related quality or life.
Considering the treatment goals, please describe goals (needs) that are not being met by currently available treatments.
Pembrolizumab monotherapy: Currently there are no agents that have specific approval for treatment of recurrent/progressive MMRd/MSI-H endometrial cancer. At time of recurrence there are limited chemotherapy options and trial of carboplatin/taxol followed by Adriamycin at progression. There is currently no standard of care for these patients. Most patients do not response to available treatments and become refractory to current treatment options. Treatments are needed that are better tolerated.
Lenvatinib in combination with Pembrolizumab: Currently there are no agents that have specific approval for treatment of recurrent/progressive endometrial cancer. At time of recurrence there are limited chemotherapy options and trial of carboplatin/taxol followed by Adriamycin at progression. There is currently no standard of care for these patients. Most patients do not response to available treatments and become refractory to current treatment options. Treatments are needed that are better tolerated.
Which patients have the greatest unmet need for an intervention such as the drug under review?
Pembrolizumab monotherapy: Patients with MMRd/MSI-H EC would have the greatest unmet need. There is current no options for MMRd/MSI-H endometrial cancer in the recurrent setting after platinum-based therapy.
Lenvatinib in combination with Pembrolizumab: There are current no options for endometrial cancer in the recurrent setting after platinum-based therapy. All patients with recurrent/progressive endometrial cancer post-platinum therapy would have the greatest unmet need.
How would the drug under review fit into the current treatment paradigm?
Pembrolizumab monotherapy: There is no established second line treatment paradigm for these patients. It would replace potential retreatment with carboplatin/taxol or adriamycin.
Lenvatinib in combination with Pembrolizumab: There is no established second line treatment paradigm for these patients. It would replace potential retreatment with carboplatin/taxol or adriamycin.
Please indicate whether or not it would be appropriate to recommend that patients try other treatments before initiating treatment with the drug under review. Please provide a rationale from your perspective.
Pembrolizumab monotherapy: No, we would not recommend other treatments since there are no other approved second line therapies for patient population. This would be the preferred option post platinum therapy at time of recurrence after failing chemotherapy.
Lenvatinib in combination with Pembrolizumab: No, we would not recommend other treatments since there are no other approved second line therapies for patient population. This would be the preferred option post platinum therapy at time of recurrence after failing chemotherapy.
How would this drug affect the sequencing of therapies for the target condition?
Pembrolizumab monotherapy: There is no current second line option and this would provide patients a second-line option. After failing platinum-based therapy, proceed to pembrolizumab monotherapy.
Lenvatinib in combination with Pembrolizumab: There is no current second line option and this would provide patients a second-line options. After failing platinum-based therapy, proceed to pembrolizumab in combo with lenvatinib.
Which patients would be best suited for treatment with the drug under review?
Pembrolizumab monotherapy: Individuals with MMRd)/MSI-H endometrial cancer (EC) that have progressed after platinum-based chemotherapy (after adjuvant chemotherapy in advanced stage or after chemotherapy for recurrent disease).
Lenvatinib in combination with Pembrolizumab: All EC patients that have recurred or progressed after platinum-based chemotherapy.
How would patients best suited for treatment with the drug under review be identified?
Pembrolizumab monotherapy: MMRd/MSI-H and evidence of recurrence on imaging (CT, MRI, PET Scan), biopsy, and examination. Immunohistochemisty for MMR is performed reflexively on all newly diagnosed cases of EC in Ontario and therefore MMRd patients are easily identified at time of recurrence/progression.
Lenvatinib in combination with Pembrolizumab: Evidence of recurrence on imaging (CT, MRI, PET Scan), biopsy, and examination.
Which patients would be least suitable for treatment with the drug under review?
Pembrolizumab monotherapy: Patients that are contraindication to immunotherapy, chemo-naïve, and MMR intact.
Lenvatinib in combination with Pembrolizumab: Patients that are contraindication to immunotherapy or Lenvatinib and chemo-naïve.
Is it possible to identify those patients who are most likely to exhibit a response to treatment with the drug under review?
Pembrolizumab monotherapy: Yes. Reflex MMR testing.
Lenvatinib in combination with Pembrolizumab: While a greater benefit from treatment was seen in MMRd, all patients regardless of MMR status should achieve benefit.
What outcomes are used to determine whether a patient is responding to treatment in clinical practice?
Pembrolizumab monotherapy: Imaging, clinical exam, and symptomatic improvement.
Lenvatinib in combination with Pembrolizumab: Imaging, clinical exam, and symptomatic improvement.
What would be considered a clinically meaningful response to treatment?
Pembrolizumab monotherapy: Reduction in the frequency or severity of symptoms, improvement of symptoms, disease response or stability.
Lenvatinib in combination with Pembrolizumab: Reduction in the frequency or severity of symptoms, improvement of symptoms, disease response or stability.
How often should treatment response be assessed?
Pembrolizumab monotherapy: As per standard of care.
Lenvatinib in combination with Pembrolizumab: As per standard of care.
What factors should be considered when deciding to discontinue treatment?
Pembrolizumab monotherapy: Disease progression or intolerable side effects.
Lenvatinib in combination with Pembrolizumab: Disease progression or intolerable side effects.
What settings are appropriate for treatment with the drug under review?
Pembrolizumab monotherapy: Hospital (outpatient clinic)
Lenvatinib in combination with Pembrolizumab: Hospital (outpatient clinic)
For non-oncology drugs, is a specialist required to diagnose, treat, and monitor patients who might receive the drug under review?
Not applicable.
Pembrolizumab monotherapy: This therapy provides high response rate in long term responders. The current chemotherapy does not provide a durable response. More tolerable toxicity profile compared to alternatives.
Lenvatinib in combination with Pembrolizumab: This therapy provides high response rate in long term responders. The current chemotherapy does not provide a durable response. More tolerable toxicity profile compared to alternatives.
To maintain the objectivity and credibility of the CADTH drug review programs, all patients in the drug review processes must disclose any real, potential, or perceived conflicts of interest. This conflict of interest declaration is required for participation. Declarations made do not negate or preclude the use of the clinician group input. CADTH may contact your group with further questions, as needed. Please refer to the Procedures for CADTH Drug Reimbursement Reviews (section 6.3) for further details.
Did you receive help from outside your clinician group to complete this submission?
The DAC received secretariat support from Ontario Health-Cancer Care Ontario provincial drug reimbursement specialist.
Did you receive help from outside your clinician group to collect or analyze any information used in this submission?
No.
List any companies or organizations that have provided your group with financial payment over the past two years AND who may have direct or indirect interest in the drug under review. Please note that this is required for each clinician who contributed to the input.
Name: Dr. Sarah Ferguson
Position: OH-CCO Gynecological Drug Advisory Committee Lead
Date: 08/12/2021
COI Declaration for OH-CCO Gynecology Cancer Drug Advisory Committee — Clinician 1.
Name: Dr. Stephen Welch
Position: OH-CCO Gynecological Drug Advisory Committee Member
Date: 08/12/2021
COI Declaration for OH-CCO Gynecology Cancer Drug Advisory Committee — Clinician 2.
Name: Dr. Josee-Lyne Ethier
Position: OH-CCO Gynecological Drug Advisory Committee Lead
Date: 08/12/2021
COI Declaration for OH-CCO Gynecology Cancer Drug Advisory Committee — Clinician 3.
Name: Dr. Julie Ann Francis
Position: OH-CCO Gynecological Drug Advisory Committee Lead
Date: 08/12/2021
COI Declaration for OH-CCO Gynecology Cancer Drug Advisory Committee — Clinician 4.
Name: Dr. Leah Jutzi
Position: OH-CCO Gynecological Drug Advisory Committee Lead
Date: 08/12/2021
COI Declaration for OH-CCO Gynecology Cancer Drug Advisory Committee — Clinician 5.
Copyright © 2023 - Canadian Agency for Drugs and Technologies in Health. Except where otherwise noted, this work is distributed under the terms of a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International licence (CC BY-NC-ND).
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