Considering Triplet Therapy for Nondriver NSCLC - Episode 3

Nondriver NSCLC: Utilizing KEYNOTE-189's Triplet Regimen

Anne Tsao, MD:Pemetrexed maintenance has been studied in non—small cell lung cancer previously, and there clearly was progression-free survival and overall survival benefit with the use of pemetrexed maintenance after a platinum doublet. The KEYNOTE-189 trial builds off that, where it adds in pembrolizumab to the pemetrexed maintenance. Clearly, there was a PFS and overall survival benefit. We certainly advocate giving pemetrexed and pembrolizumab as maintenance therapy. Now, if a patient has an autoimmune adverse event, you could certainly drop pembrolizumab, or if they have toxicity from the pemetrexed, you could just continue pembrolizumab maintenance therapy.

Regarding the regimen of the triplet with carboplatin/pemetrexed/pembrolizumab, I will usually give about 4 to 6 cycles, and it really depends on the patient’s response. If they are still shrinking dramatically after 4 cycles and their performance status is still good, I will go to 6 cycles of therapy. But if they plateau, I usually stop at 4 and just go to maintenance therapy. In the case of how long to give these treatments for, the prior studies with maintenance pemetrexed continued until patients developed progression of disease. We don’t know how long we should be giving pembrolizumab maintenance therapy. Some studies have shown in other tumor types that perhaps 1 year or 1 and a half years may potentially be enough. In KEYNOTE-189, they gave pembrolizumab for a total of 35 cycles of therapy, so we currently do that in clinical practice. But there are trials ongoing right now to determine what the optimal time frame is to give maintenance pembrolizumab and pemetrexed.

The triplet regimen can be tough to give, so you do have to give it to a patient who has a reasonable performance status. By this, I do include PS2 patients because they have high disease burden. For patients who are in very good health and have their cancer, but they just have a lot of it, this is certainly an appropriate regimen to give. The platinum pemetrexed backbone is very well tolerated, and we have those data. Again, the addition of pembrolizumab to this does not significantly increase toxicities. If you look at the KEYNOTE-189 trial, the grade 3 adverse events were pretty equivalent between the 2 arms. There was a slightly increased risk of rash and diarrhea, which are typical autoimmune events, as well as febrile neutropenia. I do always caution patients that there could be some slightly higher kidney toxicity, 5% versus 3%. But certainly, this is a regimen that’s very well tolerated overall and does not appear to have too much additional toxicity beyond a platinum doublet.

Adding pembrolizumab to chemotherapy does appear to increase rash, diarrhea, and febrile neutropenia. These are to be expected. Pembrolizumab is a checkpoint inhibitor. It stimulates the immune system, and as always, you have to watch for any type of autoimmune reaction. I usually counsel patients that they can get any type of “itis,” any inflammation anywhere in the body. Typically, with checkpoint inhibitors, you have to watch the thyroid function. Patients could get hyperthyroidism or hypothyroidism. Those are usually the most common adverse events, including rash, and you could get a small percentage of colitis as well.

Now, in terms of management, early detection is very important. Education of the patient is crucial because the minute that they develop an itis, we have to monitor it. If it is something like a rash, you could use topical steroids as long as it’s not severe. But if it does progress, you do have to give them systemic steroids and hold off on any immunotherapies. For colitis, it is very important to make sure the patient stays hydrated, and I also have a very low threshold for initiating steroids in this case. There are treatment algorithms that are posted online for all the checkpoint inhibitors that can be followed.

In terms of febrile neutropenia, I have given OnPro (pegfilgrastim) as a protective agent for my patients who were receiving the triplet regimen, to decrease their risk of febrile neutropenia. I sometimes will do this prophylactically in our patients who I think are at higher risk. In terms of renal toxicity, hydrating the patient and educating them on staying hydrated is very important. Usually, you have to check their labs before every single treatment, and you can pick this up pretty quickly.

In KEYNOTE-189, there was no increase in the percentage of patients who had grade 3 or higher toxicity. It was pretty equivalent. There was a little bit of a difference between the side effect profiles. Obviously, you get more immune-related events, so rash, diarrhea, and febrile neutropenia are the ones you watch out for. And then there was a slightly higher renal toxicity, but beyond that, it was very well tolerated, and there was nothing too significant with that regimen.

Transcript edited for clarity.


A 64-Year-Old Woman With Metastatic NSCLC

  • A 64-year-old woman reported having cough and shortness of breath on exertion for the past 2 years, but now having persistent symptoms even without exertion.
    • PE: revealed diminished breath sounds and minimal expiratory wheezing in right lung; not physically fit
    • PMH: mild hypertension well managed on lisinopril
    • SH: smoker, 15 pack-years
  • CT scan revealed 2 masses in RUL and several small masses in the liver
  • Biopsy of right lung mass confirmed grade 2 adenocarcinoma
    • EGFRnegative,KRASnegative
    • IHC negative forALK-rearrangement,ROS1-rearrangement
    • PD-L1 TPS: 56%
  • PET scan showed multiple areas of FDG uptake in liver, SUVmax, 7.8
  • Brain MRI, negative for metastases
  • Diagnosis: stage IV lung adenocarcinoma
  • Patient started on treatment with pembrolizumab/pemetrexed/carboplatin