Coleman Discusses Platinum Rechallenge and Lenvatinib Dosing for Endometrial Cancer

Robert Coleman, MD (Moderator)

Chief Medical Officer

Vaniam Group

Spring, TX

CASE SUMMARY

A 64-year-old postmenopausal woman presented with abnormal uterine bleeding for approximately 3 months. She has 2 grown children and no known family history of cancer. Her body mass index is 32, and she has hypertension well controlled with medication. Physical examination showed a large uterus and right lower quadrant abdominal tenderness on palpation. Endometrial biopsy led to a diagnosis of endometrioid adenocarcinoma of International Federation of Gynecology and Obstetrics (FIGO) grade 1.

She underwent extralevator abdominoperineal resection, total abdominal hysterectomy, bilateral salpingo-oophorectomy, and sentinel lymph node biopsy (SLNB). Examination showed grade 2 endometrioid adenocarcinoma, with 0 nodes positive for disease from SLNB, that was invasive 2.1 cm of 2.3 cm in the myometrium; lymphovascular invasion present; and estrogen receptor–positive (ER+) disease by immunohistochemistry. Her staging was FIGO stage IB (T1b, N0, M0), grade 2 endometrial adenocarcinoma. Notable molecular features were microsatellite stable, mismatch repair (MMR) proficient, HER2 negative, and ER+.

She received postoperative radiotherapy: vaginal cuff brachytherapy at a dose of 21 Gy in 3 fractions. Fourteen months after completing radiotherapy, she presented with new right lower extremity edema and right hydroureter. There was no evidence of distant metastases on radiologic imaging. Carboplatin/paclitaxel chemotherapy was initiated. Treatment was well tolerated, and 4 months after initiation, she had no evidence of disease (NED) on PET scan, with complete resolution of symptoms.

Twelve months later, disease relapse is documented on routine follow-up, with metastases to the paraaortic lymph nodes and lung. The patient reported having had a chronic cough that she had attributed to allergies. Bronchoscopy with biopsy results revealed endometrial carcinoma cells.

COLEMAN: For those who would give repeat paclitaxel and carboplatin, what criteria do you use? There is no wrong answer here. Before we had lenvatinib [Lenvima] and pembrolizumab [Keytruda], most physicians would repeat paclitaxel and carboplatin because we don’t have many great choices for the nontaxane, platinum-based strategies.

RICH: The 2 elements that would influence my choice of
re-treating her with carboplatin and paclitaxel [would be] both a deep response to the initial therapy [and that] she had NED in the 1-year interval. No one talked about neuropathy or how it was tolerated, but in an essentially incurable disease, it’s all about trying to stretch out therapies. With a deep and durable response to what I presume was a well-tolerated therapy, it’s worthwhile to…try treating and reimaging and see where we stand. I suspect that would not result in a substantial survival reduction.

COLEMAN: As common as this situation is, you’d be surprised at how little data we have in platinum retreatment. We do have some, [but] they are not quite as good.^1,2 Some patients respond, but…the toxicities that come from previous treatment play into that decision. Hopefully, with a long treatment-free interval, a lot of symptoms would ameliorate, but she might lose her hair again, and she may not want to. Those are important considerations in making a treatment decision.

Performance status is another factor in recurrent endometrial cancer that we don’t appreciate. Many of these patients who have recurrent disease are relatively sick. Unlike ovarian cancer in similar-aged patients, these patients [do] not [have] robust [response] for getting multiple subsequent lines of therapy. It’s not uncommon in the United States to have 7 or 8 lines of therapy in a patient with ovarian cancer, but it is extraordinarily rare to see that in a patient with endometrial cancer. They [have] less robust [response] and don’t tolerate multiple lines of therapy. So I agree with you. I try to give the best therapy I can as early as I can, but you’ve got to look at the total clinical picture.

NABRINSKY: Is there anyone with good experience with bevacizumab [Avastin] as a single agent vs paclitaxel? I had very robust and lasting responses over the past 2 years.

COLEMAN: We did a 3-arm trial. It was published finally;
it is called GOG-0086P [NCT00977574], and 2 of the
3 arms ended up getting bevacizumab.... We didn’t do a plus or minus for bevacizumab, and we [previously] had about a 10% [to] 14% overall response rate with single-agent bevacizumab in endometrial cancer.³ It’s not quite as robust as it is in ovarian cancer, but in the GOG-0086P trial, the PFS [progression-free survival], OS [overall survival], and response characteristics weren’t much better than just paclitaxel and carboplatin.⁴ I’ve done it myself, but it doesn’t seem to have the same impact we saw in ovarian cancer. Maybe we haven’t used it in the right combination yet.

MENER: I’m not sure what other participants’ experience has been, but my experience with a reduced dose of lenvatinib is [that] it’s a remarkably well-tolerated regimen.

DISCUSSION QUESTION

• What has been your experience with lenvatinib plus pembrolizumab?

COLEMAN: It’s been out for about 3 years now, [with] 2 years [of] regular approval.5 Does anybody have much experience with it?

MENER: [I have used it] half a dozen times. I have 1 patient who was [in] the confirmatory trial. She was the last one enrolled. She had a complete response [CR], and she is still in a CR. She’s long since finished her pembrolizumab. She’s still on the lenvatinib, and I wonder how long she will continue it.

COLEMAN: For me, it’s the other way around. You can’t keep them on the lenvatinib, but they can make it through their pembrolizumab dosing. That’s impressive. That’s a good case.

MENER: She’s doing great. My experience has been that when you…reduce lenvatinib to 8 mg, it is well tolerated. She has had a fabulous response. She ended up getting proteinuria and hypertension both at the higher doses and at the low dose as well. The 4 or 5 patients whom I’ve treated off trial started at a reduced dose. I haven’t seen anyone tolerate the full dose.

COLEMAN: Yes, it’s been tough.

MENER: I don’t know what your experience is, but I’m now starting patients at 12 mg [of lenvatinib and] then [going] down from there.

COLEMAN: So you’re starting patients at a lower dose. A lot of us are doing that. I’ve always been concerned about altering the regimen that’s supported by the clinical trial [data from KEYNOTE-775 (NCT03517449)] to a different dosing and hoping we see the same results.⁶ But when you have two-thirds of your patients requiring a dose reduction after the first cycle, I can see how physicians go in that direction.

SOLANKI: I was puzzled by the idea that patients with microsatellite instability–high [MSI-H] disease were included in the study and [were] exposed to lenvatinib when they would have done perfectly well with pembrolizumab alone.

COLEMAN: That wasn’t available universally when the study was first designed. Pembrolizumab as a single agent first came in as an MSI-high approval across tumor types and was converted later to an endometrial cancer indication. As the study matured, fewer patients went on it when they were known to have a deficient MMR status and could get pembrolizumab alone.

CASE UPDATE

The patient receives lenvatinib plus pembrolizumab.

DISCUSSION QUESTION

• Given the data and guidelines, do you agree with the treatment plan for the patient in this case?

COLEMAN: She got paclitaxel plus carboplatin followed by lenvatinib and pembrolizumab. The only question was whether to reinduce with paclitaxel and carboplatin, which wouldn’t be wrong. Our patient had 2 characteristics. She had a good response to paclitaxel and carboplatin the first time, which is unusual. Second, she had a platinum-free interval of 14 months. When is that not good enough? What if it’s 6 or 8 months?

RICH: I would say a minimum of 6 months, but it also depends on the extent of her recurrence. If she’s showing up with some lung nodules and a marker, I’m going to feel comfortable re-treating her. If she shows up with liver metastases or symptomatic bone metastases, then she’s probably going to try to get the best therapy. The experience I have in renal cell carcinoma [RCC] is a drug that is dose reduced 60% to 80% of the time [and] still has substantial benefit.

It doesn’t make any sense to me. If the dosing was essential to stay at 20 mg, then [because] we’re all dose reducing, you wouldn’t see the argument that it’s the first month that is critical. I have trouble swallowing that. A lot of these patients are older women. They don’t have great [performance status], and the constitutional toxicity of [lenvatinib] is hard [to tolerate]. If Dr Mener is having success with [lenvatinib], it must be because he’s dose reducing up front, because this drug is full of complaints of “I’m exhausted,” “I’m not eating,” “I’m losing weight,” and “I [had] to start another blood pressure medication.” It’s an impressive agent, but it feels like capecitabine [Xeloda] to me…. I know the data say I’m supposed to use 2500 mg/m²
daily, but I don’t think anyone…does that anymore. Did anything suggest that there are subgroups that might benefit from this combination? [Is there] anything to fine-tune our approach?

COLEMAN:Not for dosing. There were some prognostic cohorts in that group, the strongest of which is those who had deficient MMR. They had the greatest difference across [findings from] the whole trial [From the Data⁶]. But the subgroups all line up with the overall treatment results of the study, just as you mentioned.

MENER: About starting low: Not that there’s no change in efficacy, but we’re using this in a palliative setting, so balancing quality of life is an important aspect. I stick to starting everybody at 12 mg, and if they’re having no adverse effects, then we can dose escalate. Starting at 12 mg and ending up at 8 mg has had great outcomes.

COLEMAN: I’m not arguing with you at all. I have gone through this myself; it is tricky to do.

SOLANKI: Why aren’t we testing step-up dosing like we did for regorafenib [Stivarga] in colon cancer, for example, where the full dose was extremely toxic and it wasn’t given for a long enough time to show any benefit? It was approved based on the hazard ratio, which was positive. [It was] not based on response rate or anything else. But nobody uses the prescribed dose anymore. Mayo Clinic did a study, and they found the step-up dosing of regorafenib.⁷ You take them up to a particular dose and leave [it] there if that’s all they [can] tolerate. Why can’t we do that with a drug like lenvatinib? In RCC, [my] experience has been the same. About 70% of the patients undergo dose modification in the first month.

COLEMAN: It’s very similar. I think the issue is not so much the step-up [dosing]. There was concern that in endometrial cancer you don’t have a lot of time, because we lose almost 50% of our patients by the second assessment. There’s not a lot of time to titrate. On the other hand, this is a great example of why dose optimization is so critical in drug development, and this is now part of the normal development of new drugs. The FDA [Oncology Center of Excellence] Project Optimus is a good example of why it needs to be done.

SOLANKI: Drug companies should test their agents at different dose levels to see whether we can find the optimal dose for each situation, because we are giving everybody the same dose and everybody’s getting [toxicities]…in the first month.

Some of them have blood pressure problems that are very hard to control. I know from discussions at previous meetings that some of the patients had severe hypertension with complications, and most of us were not able to manage that kind of hypertension plus the diarrhea issue. Other gastrointestinal issues are severe [as well].

Do we know what the delivered dose was in this study? One can plan any dose they want, but what on average did the patient end up getting?

COLEMAN: That’s a good question.

SOLANKI: [Findings from] most studies don’t report it. It should be a requirement. It’ll give us an idea. Because I think the patient who stayed on a particular dose the longest may be on the right dose.

COLEMAN: The [median] dose intensity for lenvatinib [in KEYNOTE-775] was approximately 14 mg.⁶

SOLANKI: I’ve heard some of your colleagues say that they start at 14 mg.

COLEMAN: They do. That’s exactly right.

SOLANKI: It may have been based on that kind of information.

COLEMAN: Right. The subgroups were all consistent with the overall trial results. So nothing stood out as a way of optimizing the dosing there.

_References

_{1. Rubinstein M, Halpenny D, Makker V, Grisham RN, Aghajanian C, Cadoo K. Retreatment with carboplatin and paclitaxel for recurrent endometrial cancer: a retrospective study of the Memorial Sloan Kettering Cancer Center experience. Gynecol Oncol Rep. 2019;28:120-123. doi:10.1016/j.gore.2019.04.002}

_{2. Souza RP, Soares GP, Lage LV, et al. The role of platinum rechallenge as second line chemotherapy for metastatic endometrial carcinoma. J Clin Oncol. 2016;34(suppl 15):e17108. doi:10.1200/JCO.2016.34.15_suppl.e17108}

_{3. Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29(16):2259-2265. doi:10.1200/JCO.2010.32.6397}

_{4. Thiel KW, Devor EJ, Filiaci VL, et al. TP53 sequencing and p53 immunohistochemistry predict outcomes when bevacizumab is added to frontline chemotherapy in endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2022;40(28):3289-3300. doi:10.1200/JCO.21.02506}

_{5. FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. FDA. July 21, 2021. Accessed June 9, 2023. https://bit.ly/3N6Jkoi}

_{6. Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330}

_{7. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4}