A Chemoimmunotherapeutic Approach to Nondriver NSCLC - Episode 3

Administering the KEYNOTE-189 Regimen in Nondriver mNSCLC

September 20, 2018

Mark A. Socinski, MD:The design of KEYNOTE-189 was a placebo-controlled 2:1 randomization, meaning that 2 patients got randomized to the investigational arm versus 1 to the control arm. The control arm was carboplatin/pemetrexed with placebo, since it was a placebo-controlled trial. Carboplatin-pemetrexed is a very standard FDA [US Food and Drug Administration]-approved regimen. No one would argue with that as a control arm. The investigational arm, and again, it was a 2:1 randomization, gave patients carboplatin-pemetrexed plus pembrolizumab. Patients on the control arm were allowed to cross over at the time of progression. And in fact, about 40% of the patients getting carboplatin-pemetrexed did subsequently receive pembrolizumab.

The trial had 2 primary endpoints: overall survival and progression-free survival. The trial met both. To me, the most meaningful number is a hazard ratio for overall survival of, I believe, 0.49, or about 0.5, suggesting a 50% reduction in the risk of death from lung cancer as a result of combining the immunotherapy with carboplatin-pemetrexed. It was actually quite impressive in terms of the Kaplan- Meier curves. And that hazard ratio, we don’t see very many hazard ratios that have that dramatic of an effect.

A very similar effect was seen on progression-free survival. The response rates on carboplatin/pemetrexed alone were about 18%. The response rates with the addition of pembrolizumab with the same chemotherapy were around 48%. So, very impressive difference in tumor shrinkage. And this was really a trial that showed that all the outcomes that we would want to see—tumor shrinking, control of the cancer in terms of progression-free survival—and ultimately those 2 things driving overall survival in such a significant manner, I think, are really notable.

The administration issues with regard to this regimen to me are not very prohibitive. Carboplatin is a drug that we give over about 30 to 40 minutes every 3 weeks. Pemetrexed is the drug that is a 10- to 15-minute infusion. Again, once every 3 weeks. And pembrolizumab is a flat dose, 200 mg IV, over an hour every 3 weeks. So, each of the drugs is given once every 3 weeks, so a relatively convenient regimen.

I typically would give 4 cycles of those 3 drugs in patients who have responding or stable disease. And this was included in the trial design for what we would refer to as the maintenance portion of the trial, which allowed you to continue both the pemetrexed as well as the pembrolizumab for maintenance therapy, until the time of disease progression or unacceptable toxicity.

So, in terms of the administration issues, I actually really don’t think there are any major issues. It’s convenient, every 3 weeks. From the time the patient hits the infusion chair to the time they’re out of the chair should be in the 3- to 4-hour range, maybe a little over 4 hours so that’s half a day. So, I honestly don’t think that it’s really prohibitive from that aspect.

In terms of managing patients and the toxicity in, you know, would there be circumstances in which you would think about discontinuing 1 of the component drugs. Well if I felt the toxicity was prohibitive and relative to the agent; for instance, if patients were diagnosed with grade 3 or4 colitis as an adverse effect, a well-known [adverse] effect of immunotherapy, I would discontinue the pembrolizumab.

Pemetrexed given over a long period of time can sometimes cause problems with peripheral edema, excessive lacrimation, skin rash, anemia, fatigue, these sorts of things. If I felt that the primary adverse effect of the drug was prohibitive, I would discontinue the pemetrexed, if I felt that the toxicity was related to that.

I always say to my particularly when their cancer is controlled, the treatment can’t be worse than the disease itself. If you respond and your disease is controlled, you typically aren’t having disease-related symptoms. So your chemotherapy adverse effects have to be very well tolerated to justify continuing on. If they’re not, then I would try to make an assessment of what I thought was causing the toxicity, and then I would discontinue that component of the regimen.

Transcript edited for clarity.

A 66-Year-Old Man With NSCLC

May 2018: H&P

  • A 66-year-old man presented to primary care with complaints of persistent cough and shortness of breath with easy exertion.
    • PE: Average height, very thin (BMI = 18 kg/m2); says he has been losing weight although not dieting; mild fever (100.6 degrees); intermittent hemoptysis
    • Lab results: CrCL 75 mL/min; A1C 6.8%; WBC 15K/µL
    • PMH: HTN managed on atenolol; former smoker (30 pack-years); attributes cough to smoking but has persisted for 3 years now since he quit
  • Primary care suspected bronchitis and prescribed amoxicillin; referred to pulmonology

June 2018: Pulmonology evaluation

  • Pulmonologist evaluated patient for COPD: diminished lung function on spirometry
  • CT revealed a 3-cm mass in left lung and multiple (<2 cm) masses in right lung, pleura, and axial lymph nodes; patient referred to oncology.

July 2018: Oncology exam

  • Biopsy identified adenocarcinoma in left lung with lymph node and pleural involvement
  • Molecular testing:
    • ALK& ROS1 rearrangement, negative
    • EGFR, KRAS wild-type
    • KRAS negative
    • PD-L1 TPS: 45%
  • Additional testing: Abdominal CT, NED; Brain MRI, NED
  • Diagnosis: Stage IVA lung adenocarcinoma without molecular drivers

August 2018

  • Patient begins treatment with pemetrexed/carboplatin plus pembrolizumab 200 mg q3 wks