Discussion of IMpower133 and CASPIAN Trials

Jyoti D. Patel, MD:In 2019, I think we’re really at an inflection point in the treatment of patients with small cell lung cancer. We have great evidence showing that 2 immunotherapies added to chemotherapy improved survival. The first trial that was presented was the IMpower133 trial, which looked at chemotherapy—carboplatin and etoposide, or cisplatin-etoposide—with the drug atezolizumab, a PD-L1 [programmed death-ligand 1] inhibitor.

The second trial was the CASPIAN trial, which was partially reported. It is actually a trial for which we’re waiting for another arm to be reported, but patients with extensive-stage small cell cancer were randomized with chemotherapy with carboplatin-etoposide up to 4 cycles versus carboplatin with etoposide plus durvalumab, and those 2 arms have been reported. The third arm of carboplatin-durvalumab and tremelimumab is ongoing for events. And so that’s certainly an exciting sign.

The 2 arms that have been reported—the standard arm of chemotherapy and the durvalumab arm—gave us confirmatory evidence that immunotherapy with chemotherapy improved survival.

Interestingly, between the CASPIAN study and IMpower133 study, the standard-of-care arm—the carboplatin-etoposide arm or the platinum-etoposide arm—showed an overall survival of 10.3 months in both trials. We think that’s a true standard, and we can say that these trials show what survival expectations are sort of reasonably held at in a large number of patients. There’s no arm that was underperforming.

In the CASPIAN trial, with the addition of durvalumab, survival improved to 13 months. That is a significant improvement. We see a hazard ratio that’s robust. And that is leading to a lot of excitement about the addition of immunotherapy. This was a little better than what was seen with the atezolizumab study, or IMpower133. Atezolizumab also improved survival with a solid hazard ratio, but there are some subtle differences in the arms.

If we look at those subtle differences, in the IMpower133 study, if patients had brain metastases, they had to have treatment up front. For patients in the durvalumab study and the CASPIAN study, patients could have untreated asymptomatic brain metastases.

We think about patients with small cell lung cancer and how we approach them in clinical practice. We treat the brain metastasis infrequently, unless they’re profoundly symptomatic. There generally are approaches to treat with chemotherapy, because we know these chemotherapies have brain penetration and we’ll see a systemic response. And so that patient population is a little different.

Moreover, patients in the CASPIAN study were able to get PCI [prophylactic cranial irradiation] in the standard arm. Only about 10% of patients did. If they didn’t have brain metastases, a small number of patients were able to do so.

In both studies, systemic chemotherapy stopped at 4 cycles. Traditionally, we often went to 6 cycles when we had no other therapies. But now, as we’ve been doing in non—small cell lung cancer, chemotherapy tends to be a little more truncated.

The patient populations in both studies were good performance status patients. I think that’s who we generally see in phase III trials when we enroll a patient, recognizing that across the country and with access to care there’s great variance in how we meet patients with non—small cell lung cancer.

There are cohorts of patients who will get their initial therapy for small cell lung cancer in the hospital, for example. Those patients were not included in these trials. Perhaps these patients were a little better than those who we see in practice. I think that the paradigms—we can certainly expand to the patients we see.

Transcript edited for clarity.

Case: A 73-Year-Old Female With Stage IV SCLC

Initial presentation

• A 73-year—old woman presented with shortness of breath, productive cough, chest pain, fatigue, anorexia and an 18-lb weight loss.
• PMH: HTN
• SH: Elementary school teacher; 50 pack year smoking history; quit 6 years ago; married with 2 children and her first grandchild on the way.
• PE: Dullness to percussion, decreased breath sounds, BMI 17

Clinical workup

• Imaging:
  • Chest x-ray showed a hilar mass and a 5.4cm right lower lobe mass
  • Chest/abdomen/pelvic CT scan revealed mediastinal adenopathy, right lower lung lobe mass, suspicious liver lesions
  • PET scan showed activity in the left upper lobe mass and supraclavicular nodal areas and liver lesions
  • No metastases to brain on MRI
• IR biopsy of liver revealed small cell lung cancer
• Staging: T3N3M1 - IVb
• ECOG PS 1

Treatment

• Concurrent durvalumab with carboplatin/etoposide; has completed 4 cycles
• Developed constipation and nausea after second cycle (constipation successfully treated with increased oral hydration and docusate; nausea treated with ondansetron)
• Repeated chest/abdomen/pelvis CT with contrast after every 2 cycles demonstrated significant response. After 4 cycles patient started maintenance durvalumab for 6 months
• Continued durvalumab every 4 weeks, with CT scans at 3 and 6 months