Trametinib (Mekinist®)—Low-Grade Serous Ovarian Carcinoma

Low-grade serous carcinomas of the ovaries or peritoneum are uncommon but not rare, accounting for about 5% to 10% of all serous cancers; the vast majority (~90%) of serous cancers are high grade.¹ Features of low-grade serous carcinoma include a more indolent course and decreased responsiveness to conventional cytotoxic chemotherapy. The prognosis for patients with low-grade serous ovarian carcinoma is significantly better compared with that for those with high-grade disease, David M. Gershenson, MD, told JNCCN 360. Dr. Gershenson is Professor of Gynecologic Oncology at MD Anderson Cancer Center, Houston. Most low-grade serous ovarian carcinomas, perhaps 70%, are diagnosed at an advanced stage, and 70% of diagnosed cases will eventually relapse. Median overall survival for patients with low-grade serous ovarian carcinoma is 100+ months, whereas the median overall survival for those with high-grade disease ranges between 40 and 60 months, reported by different investigators.^2,3

A Binary Grading System: Low- Versus High-Grade Disease

Low-grade serous carcinoma tends to be diagnosed in women who are somewhat younger than the overall population of patients with ovarian cancer. “In our original studies,” Dr. Gershenson noted, “patients were about 10 to 15 years younger on average compared with those who developed high-grade ovarian cancer.”

“Pathologists and our group of clinicians in the Department of Gynecologic Oncology and Reproductive Medicine at MD Anderson developed a binary grading system for serous ovarian cancers: low grade and high grade. We started using it in the 1990s, and after 10 years of experience, we published our findings in 2004,”⁴ Dr. Gersenson said. Over the next few years, that binary system was embraced by gynecologic pathologists, and in 2014, it was adopted by the World Health Organization.⁵

“Recently, we have seen patients in their 20s and 30s and even in their teens. However, in general, patients with low-grade serous carcinoma are in their mid-40s to mid-50s,” Dr. Gershenson observed.

In general, patients with low-grade serous carcinoma are in their mid-40s to mid-50s.

Historically, until this binary grading system was developed, low-grade serous carcinoma was treated exactly like all other types of ovarian cancer. “Once an awareness of the distinction emerged, a divergence in treatment also began to develop, and protocols specific to the low-grade subtype were explored,” Dr. Gershenson said.

Treatment of Low-Grade Disease

Initially, most patients with a new diagnosis of low-grade serous ovarian cancer undergo debulking surgery by a gynecologic surgeon. Afterward, patients may receive adjuvant therapy.

First-line adjuvant treatment for most ovarian cancers consists of a platinum/taxane regimen alone, although recently, maintenance with PARP inhibitors or bevacizumab has also been used. However, a review of trial results revealed that treatment of low-grade serous tumors with cytotoxic regimens was not very effective. “What we realized,” Dr. Gershenson explained, “was that if maintenance with endocrine therapy was given after chemotherapy in these patients, progression-free survival was much better.”

Two Therapeutic Strategies

Two initial therapeutic strategies, reported in 2017, have been described for women with stage II, III, or IV low-grade serous carcinoma: one is carboplatin/paclitaxel chemotherapy for six cycles, followed by maintenance with the aromatase inhibitor letrozole until disease progression.³ This approach is not dissimilar from treatment for estrogen receptor–positive breast cancer.

“The other strategy, practiced at some centers, is to give letrozole monotherapy after surgery but without any chemotherapy,”⁶ Dr. Gershenson told JNCCN 360. “We now have a randomized clinical trial sponsored by the National Cancer Institute that is comparing the two strategies specifically for low-grade serous ovarian carcinoma (ClinicalTrials.gov identifier NCT04095364). These strategies are not considered for high-grade disease.”

Although low-grade serous ovarian carcinoma is generally not sensitive to chemotherapy, some patients do respond to it. “The concept of insensitivity to chemotherapy is a relative one, compared with the responsiveness of high-grade tumors.⁷ We also know that some low-grade serous carcinomas respond to endocrine therapies, resulting in stable disease for long periods,” Dr. Gershenson said.⁶ Moreover, retrospective studies from MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center have shown that bevacizumab is also active in this setting,^8,9 he continued.

Finally, Dr. Gershenson noted, some targeted agents, such as MEK inhibitors (trametinib) or even BRAF inhibitors have activity as well. [Editor’s Note: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Ovarian Cancer¹⁰ list trametinib as an option for recurrent disease but not in the primary setting. BRAF-targeted therapies are not recommended options in the NCCN Guidelines. Additionally, Dr. Gershenson observed that only about 5% of low-grade serous carcinomas involve a BRAF mutation,¹¹ which is why studies using those agents have not been initiated. A few cases have been reported of women with recurrent low-grade serous carcinoma whose tumors harbor a BRAF mutation being treated with a BRAF inhibitor.¹²] “Our armamentarium for this disease has expanded over the past 10 years on the basis of retrospective studies as well as a few clinical trials.”

Low-Grade Serous Ovarian Carcinoma: Clinical Course

“By the time trametinib is considered,” Esther L. Kannapel, APRN, told JNCCN 360, “it may be a couple of years after surgery and upfront chemotherapy.” Because low-grade disease is more indolent than high-grade disease, its effects tend to be insidious, she explained. Ms. Kannapel is a family nurse practitioner in the Division of Oncology at the University of Utah School of Medicine, Salt Lake City.

Symptoms that patients may experience with the progression of low-grade disease include bowel dysfunction and abdominal distention. These symptoms often cause decreased appetite and early satiety, which compromise a patient’s nutritional status. Because these symptoms can be attributed to benign causes, relapse is challenging to identify. Often, there is no discrete mass on imaging.

“I describe the distribution of disease to patients as being like ‘moss,’ covering stones in a riverbed,” Ms. Kannapel suggested. “Because of this, there may be alteration in bowel function, abdominal distention, and ascites before we can definitively diagnose a relapse,” she continued. And, because visual signs of relapse in low-grade disease are missing or difficult to detect, patients may be symptomatic by the time relapse is diagnosed. The result of this is often a patient has poor nutritional status and fatigue at the time of relapse diagnosis, Ms. Kannapel observed.

MEK Inhibition: Mechanism of Action

Most low-grade serous carcinomas express the estrogen receptor, and roughly half express the progesterone receptor. However, there have not been any studies that correlate the presence of these receptors with a response to endocrine therapy.¹³

“We know that the MAP kinase signaling pathway plays a prominent role in the pathogenesis of low-grade serous carcinoma,” Dr. Gershenson said. In contrast to high-grade ovarian cancer, low-grade serous carcinoma is characterized by wild-type p53—“the biology of the two subtypes is different.”¹⁴

We know that the MAP kinase signaling pathway plays a prominent role in the pathogenesis of low-grade serous carcinoma.

Explaining researchers’ interest in studying MEK inhibition in this setting, Ms. Kannapel noted: “Low-grade serous carcinomas are characterized by alterations in the MAP kinase cell signaling network, which include MEK proteins. Trametinib is a MEK inhibitor.”

The first study that was conducted with a MEK inhibitor in low-grade serous carcinoma was with selumetinib.¹⁵ It was a phase II trial of about 52 patients; the response rate was 15%. The presence of KRAS and BRAF mutations was evaluated, and “at least in that study,” Dr. Gershenson reported, “there was no correlation between the presence of mutations and response to selumetinib.”

In a second-generation study, the MILO/ENGOT-ov11 investigators looked at another MEK inhibitor, binimetinib.¹⁶ “Although negative in terms of results, that study suggested the KRAS status of the tumor might have made a difference in outcomes,” Dr. Gershenson explained. “In other words, patients with mutated KRAS might have shown greater responses.” [Editor’s Note: The NCCN Guidelines do not suggest either selumetinib or binimetinib as treatment options.]

Biomarkers of Response?

In the NRG-GOG 0281 study,¹⁷ “we are analyzing whole-exome sequencing for KRAS, BRAF, and other mutations within the MAP kinase pathway,” Dr. Gershenson said. “We anticipate having all the data and analyses later in 2020 and may be able to look at any correlations that could yield clues about potential biomarkers of response.”

In terms of current clinical practice, “we do not require that a patient’s tumor have a KRAS or BRAF mutation to be eligible for treatment with trametinib,” Dr. Gershenson added. “That could change, but even if correlations are noted, I don’t anticipate it will be an all-or-nothing situation.”

Clinical Use of Trametinib

At this time, trametinib is an option for any patient with recurrent low-grade serous ovarian carcinoma, regardless of tumor mutational status.

Based on the presentation of data from NRG-GOG 0281, trametinib was incorporated into the NCCN Guidelines,¹⁰ although it has not yet received an FDA indication.¹⁸ At this time, trametinib is an option for any patient with recurrent low-grade serous ovarian carcinoma, regardless of tumor mutational status.

Clinically, these patients are expected to survive, on average, 100 months, suggesting many will live longer. And, although they generally receive multiple lines of therapy with different cytotoxic agents and regimens, endocrine therapies, and/or bevacizumab, “they tend to be younger than other cancer populations and thus have fewer comorbidities,” Dr. Gershenson noted. Certainly, many lines of anticancer therapy, “particularly aggressive ones, will take a toll, but for the most part, patients with recurrent low-grade serous carcinoma have an excellent performance status,” he said.

Steep Learning Curve for Gynecologic Oncologists

Trametinib is a tricky drug to manage, according to Dr. Gershenson. The clinicians with the most experience using trametinib are medical oncologists who treat melanoma and non–small cell lung cancer. Therefore, some of the clinicians who were involved in the two trametinib studies for low-grade serous ovarian cancer—ie, the gynecologic oncologists—had little experience with this drug class. This is true for clinicians across the country: Practitioners who treat patients with ovarian cancer are often unlikely to have had experience with trametinib or any other MEK inhibitor.

“There is a steep learning curve when you first start using trametinib therapeutically,” Dr. Gershenson told JNCCN 360. “When I am asked to consult on a case in the community, I make sure both the patient and the physician are aware that the adverse effects of this drug class are different from those they may be familiar with.”

Common (Mild) Adverse Effects

“We diligently monitor for marrow suppression issues—such as bleeding, low white blood cell count, infection, and fever—in any patient receiving chemotherapy or another anticancer therapy,” Ms. Kannapel explained. “I also advise patients to call us promptly if they note bruising, excessive bleeding, unusual fatigue, fever, or infection.”

Fatigue was the most common side effect reported by patients who received trametinib in the clinical trial, Dr. Gershenson reported. However, it was generally not severe and was manageable, he noted.

Patients are often fatigued as a result of their disease, Ms. Kannapel pointed out, “but it may be exacerbated by trametinib treatment. We work on making sure patients are sleeping well, which may include meditation, over-the-counter options (eg, melatonin), and even prescription sleep aids. We coordinate efforts with our supportive oncology group to optimize sleep quality.”

Skin rash, usually acneiform, was also common in patients on study and sometimes required treatment interruptions and/or dose reductions. “As part of the trial,” Dr. Gershenson said, “we used a prophylactic regimen for the first 6 weeks of treatment with trametinib: 1% topical hydrocortisone cream and either topical clindamycin or oral doxycycline.” If skin rash developed or worsened after the first 6 weeks, these interventions could be continued or reinstituted. Most patients were able to manage and tolerate these rashes, but some patients decided to discontinue treatment because of them.

“Skin rashes and flare-ups of dermatologic conditions such as rosacea may occur with trametinib, as well as problems with the nails,” Ms. Kannapel also reported. “We recommend hydrating hands and feet well and being vigilant about good nail care. The sooner these issues are addressed, the better the outcomes.” 

The third most common type of adverse effect was gastrointestinal (5%–10% grade 3 in the GOG study). Nausea was common, but vomiting was less so; diarrhea or constipation was reported, as was abdominal cramping.

Typically, patients who start trametinib will report diarrhea, Ms. Kannapel pointed out. “It’s important to promptly and aggressively manage this adverse effect, with appropriate antidiarrheal medication, to prevent electrolyte disturbances and dehydration, for example. Supportive care with IV fluids and electrolytes, once the patient is seriously dehydrated, can be more cumbersome,” she explained. “I like to see patients about 3 or 4 weeks after they have started treatment, and we may do a telehealth visit, depending on how far they are from the center.”

Another side effect is nausea; it seems to present more as a “lack of appetite and taste changes rather than actual vomiting,” Ms. Kannapel said. “We are aggressive with antinausea medications and stress the importance of oral care when patients start treatment. We also advise patients to choose cold foods, which are less likely to cause nausea or trigger the sensation of taste alteration. I have found the use of antacids and antigas agents to be helpful because abdominal bloating from disease makes the GI side effects worse,” she said, noting there are also a few medications that may be tried to stimulate appetite.

We also advise patients to choose cold foods, which are less likely to cause nausea or trigger the sensation of taste alteration.

Trametinib should be taken on an empty stomach, so most patients find it convenient to take it first thing in the morning, before breakfast, Ms. Kannapel told JNCCN 360. However, “it may be worth experimenting with taking it at different times of the day or before bedtime to see whether side effects are reduced,” she suggested.

“An adverse effect many patients may not report or be aware of, “Ms. Kannapel observed, “is hypertension. Blood pressure can become elevated with trametinib.” Dr. Gershenson noted that almost 40% of patients experienced an elevation in blood pressure in the GOG study, and “grade 3 hypertension was noted in about 12%.” He added that hypertension was usually manageable, but clinicians should remain vigilant.

“If the patient is already taking an antihypertensive medication, I ask her to take her blood pressure regularly at home and to maintain a record.” These blood pressure diaries are sent to the team once a week. If blood pressure is not controlled with the current medication, “we may need to add another agent,” Ms. Kannapel said. For patients without hypertension at baseline, “blood pressure can become elevated pretty soon after starting trametinib. We try to treat any such hypertension promptly to prevent complications, such as heart failure, later on,” Ms. Kannapel advised.

Rare but Potentially Serious Side Effects

In addition to the more common, usually mild, side effects, there were three rare but potentially serious adverse events. One is retinal vein occlusion. All patients starting on trametinib should have an ophthalmologic exam to assess the retina. Thereafter, patients were asked about visual issues, such as blurred vision, at every monthly clinic visit. If visual symptoms were reported, an ophthalmologic assessment was performed, and, in some cases, treatment was interrupted. If the visual symptoms subsided, the treatment could be restarted, perhaps at a lower dose.

The second rare but serious side effect involved cardiac left ventricular function and decreased ejection fraction. Patients starting on trametinib should have a baseline electrocardiogram and echocardiogram, with repeat testing every 3 months during treatment, recommended Dr. Gershenson. If a decrease in ejection fraction improves after treatment is discontinued, “it may be possible to restart therapy.”

Finally, pneumonitis, which is also seen with other targeted treatments, immunotherapy, and PARP inhibitors, was also reported with trametinib. However, it was rare.

For patients with preexisting respiratory conditions, such as asthma or allergies, “we ensure that patients are being treated and these issues are well controlled,” Ms. Kannapel said. “Pneumonitis is a rare side effect of trametinib, but it could be much more severe or devastating in a patient with an underlying respiratory condition.”

Monitoring and Consultations

When there is a vision issue, “we always refer to ophthalmology,” Ms. Kannapel explained. However, “we often are able to handle straightforward side effects such as elevated blood pressure and skin/nail effects on our own. If the patient has an internist, we may loop that person in, noting, ‘Your patient will be starting a medication that can elevate blood pressure,’ she told JNCCN 360.

“We are fortunate to have a social worker on our team,” Ms. Kannapel said. This means patients who have transportation or child-care needs or who are caregivers for others, for example, can get assistance. Additionally, “we have a Wellness Center that patients can attend for tailored exercise programs, physical therapy, and nutritional guidance from dieticians. All of these efforts are important to helping patients improve and maintain quality of life.” Trametinib can be continued as long as it seems to be working and the “patient’s lab work and imaging (ie, stable disease on CT) look good, so we frame it as a potentially ‘chronic therapy,’” Ms. Kannapel explained.

Future Directions for Trametinib in Gynecologic Cancer

“Although I am not aware of any specific research plans,” Dr. Gershenson said, “it is inevitable that MEK inhibition will be studied in earlier lines of treatment. For instance, after surgery, it might make sense to look at trametinib for maintenance after chemotherapy or, like endocrine therapy, after surgery without chemotherapy.” 

In addition, combinations, such as a MEK inhibitor plus bevacizumab, an endocrine agent, or a CDK4/6 inhibitor, are likely to be studied, he observed. On the basis of preclinical findings that suggest synergy, “we are conducting a small study at MD Anderson looking at selumetinib plus the PARP inhibitor olaparib in patients with KRAS mutations (NCT03162627). The study population includes some patients with low-grade serous ovarian cancer.”

Words of Advice

“I would simply encourage gynecologic oncologists who are considering trametinib in eligible patients to educate themselves about its adverse effects and how to manage them. Learn about how to use prophylaxis for skin rash, for instance, and educate your teams to be vigilant about ophthalmic and cardiac effects,” Dr. Gershenson said. At MD Anderson, for example, the physician, nurse practitioner, or clinical pharmacist may receive calls from patients, and “it behooves the team to be prepared and up to speed.” Occasionally, “for difficult issues regarding adverse events, consultation with a medical oncologist who cares for patients with melanoma may be considered,” he suggested.

“It’s exciting to have another treatment option for this group of patients, especially because their tumors do not respond well to chemotherapy. I would encourage clinicians on other teams to go ahead and use it in eligible patients and to be proactive about any side effects so patients can continue with therapy,” Dr. Gershenson concluded. “If you treat most of these adverse effects promptly, you can help patients derive as much benefit as possible.”

Disclosures

David M. Gershenson, MD, has conducted research for the National Cancer Institute and Novartis; has received royalties from Elsevier and UpToDate; has consulted for Genentech and participated in the advisory board for the National Cancer Institute Clinical Trials and Translational Research Advisory Committee Guidelines Development (other than NCCN); and has reported an equity interest in Biogen, Johnson & Johnson, and Bristol Myers Squibb.

Esther L. Kannapel, APRN, has reported no conflicts of interest.

References

1. Kaldawy A, Segev Y, Laie O, et al. Low-grade serous ovarian cancer: a review. Gynecol Oncol 2016;143:433–438.
2. Gockley A, Melamed A, Bregar AJ, et al. Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstet Gynecol 2017;129:439–447.
3. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnoses, treatment and follow-up. Ann Oncol 2013;24(suppl 6):vi24–vi32.
4. Malpica A, Deavers MT, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 2004;28:496–504.
5. Kurman RJ, Carcangiu ML, Herrington CS, et al (eds). WHO Classification of Tumors of Female Reproductive Organs. Lyon, International Agency for Research on Cancer, 2014.
6. Gershenson DM, Bodurka DC, Coleman RL, et al. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol 2017;35:1103–1111.
7. Gershenson DM, Sun CC, Bodurka D, et al. Recurrent low-grade serous carcinoma is relatively chemoresistant. Gynecol Oncol 2009;114:48–52.
8. Dalton HJ, Fleming ND, Sun CC, et al. Activity of bevacizumab-containing regimens in recurrent low-grade serous ovarian or peritoneal cancer: a single institution experience. Gynecol Oncol 2017;145:37–40.
9. Grisham RN, Iyer G, Sala E, et al. Bevacizumab shows activity in patients with low-grade serous ovarian and peritoneal cancer. Int J Gynecol Cancer 2014;24:1010–1014.
10. Armstrong DK, Alvarez RD, Bakkum-Gamez JN, et al. NCCN Clinical practice Guidelines in Oncology (NCCN Guidelines). Ovarian Cancer including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2020—March 11, 2020. Accessed August 13, 2020. To view the most recent version of these guidelines, visit NCCN.org.
11. Ricciardi E, Baert T, Ataseven B, et al. Low-grade serous ovarian carcinoma. Geburtshilfe Frauenheilkd 2018;78:972–976.
12. Mendivil AA, Tung PK, Bohart R, et al. Dramatic clinical response following dabrafenib and trametinib in heavily pretreated low grade serous ovarian carcinoma patient with a BRAF V600E mutation. Gynecol Oncol Rep 2018;26:41–44.
13. Voutsadakis IA. Hormone receptors in serous ovarian carcinoma: prognosis, pathogenesis, and treatment considerations. Clin Med Insights Oncol 2016;10:17–25.
14. Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol 2016;2:482–490.
15. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. Lancet Oncol 2013;14:134–140.
16. Grisham R, Monk BJ, Banerjee S, et al. MILO/ENGOT-ov11: phase 3 study of binimetinib versus physician’s choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. IGCS meeting abstracts, Plenary 1. IGLS 19-0523. Int J Gynecol Cancer 2019;29(suppl 3).
17. Gershenson DM, Miller A, Brady W, et al. A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer. 2020 Society of Gynecologic Oncology Annual Meeting. March 29, 2020. Abstract 42.
18. Mekinist (trametinib). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/204114s016lbl.pdf. Accessed August 20, 2020.