Exploring and Combining Therapy Options

Jyoti D. Patel, MD:For all patients with cancer, we use shared decision making. We talk about what they’re doing, what they hope to do, and what their aspirations are, as well as what therapies we have and what expectations are reasonable.

Certainly for a patient for whom time is important, if there are milestones—is there a birth, is there a wedding, is there something in their life that’s very important to them—then talking about hazard ratios and really looking at the tail of the curve when we’re looking at Kaplan-Meier survival curves with these therapies, I think it’s important to say, “There’s an increased chance that you could benefit from these therapies later on. Though the lines look pretty close up front, the fact that you could benefit from immunotherapy and chemotherapy may potentiate your improvement with immunotherapy, you should probably get all these early on.”

Some patients say, “I don’t want increased toxicity. The last thing I want to do is be a burden.” This, thankfully, is a disease scenario in which a treatment option doesn’t cut back on quality of life. We await formal PROs [patient-reported outcomes] from these studies. But from what we see in terms of toxicity, there’s not a significant detriment with combination therapy. This makes a lot of sense for most people.

Other options we talk to her about: improving survival, and whether she wants to pursue PCI [prophylactic cranial irradiation] given the dearth of data that we have. We will be participating in the trial for patients with all stages of small cell lung cancer, to really get a better idea of the benefit of PCI and to understand neurocognitive decline and whether immunotherapy can help that.

There are certainly options for patients in terms of intensification, with perhaps consolidation radiation therapy in some patients. I think the goal for this patient, in particular, is to get disease response, to do these 12 weeks of chemotherapy with immunotherapy, stay on immunotherapy, and then surveil the patient for disease recurrence. Hopefully she’ll have a long time on durvalumab alone.

Although we have great data with immunotherapy up front, a lot of questions persist. We know that most patients will have progressive disease and relapse despite using 3 drugs early on. The only FDA approved second-line therapy is topotecan. Although we know it works—it’s effective, and we know a good number of patients have responses that improve survival—we’d like to see it be a little better.

Things we are focusing our efforts on are looking at targeted therapies.DLL3, for example, is a protein expressed in small cell lung cancer. The antibody drug conjugate that was targeted atDLL3, Rova-T [rovalpituzumab, tesirine], was unsuccessful. But a number of other drugs are being explored in that context, and they are combining with immunotherapy. There are bispecific antibodies as well as CAR [chimeric antigen receptor] T-cell therapies withDLL3. That’s an area of active interest.

Other therapies, like lurbinectedin, are new synthetic analogs that may be effective. In a single-arm trial, the response rate was 37%. We know that the phase III trial has been completed with Adriamycin [doxorubicin] and lurbinectedin, and we’ll wait to see what that will look like.

Then there’s more immunotherapy. If a patient has progressive disease on durvalumab or atezolizumab, is it possible we may be able to get another response with dual immunotherapy? We have good evidence in a number of trials looking at the combination of nivolumab and ipilimumab. We know that there is a tremelimumab-durvalumab study ongoing. It may be that we really need the T cells to be effective. Understanding dual immunotherapy, the checkpoint blockade after durvalumab, is an area where we need to spend some resources and time.

Both durvalumab and atezolizumab, in addition to chemotherapy, offer a great option for patients with extensive-stage disease. In real-world challenges, we certainly know what the trial showed. These were good performance status patients who had therapy with both drugs from day 1 and were able to tolerate treatment, and we know that led to overall survival benefits.

Clinically, what do we do? For example, if a patient is diagnosed in the hospital and gets a first cycle of therapy, if we know that chemotherapy works, if the patient presents to us for a second cycle of therapy and has regained performance status and is doing well, can we add the immunotherapy there? I have been. I think that’s a reasonable way forward. Certainly as we expand these drugs in greater patient populations, we’ll see which patients benefit the most.

I think questions about how we incorporate radiation with immunotherapy will be ongoing. Again, we know radiation can be helpful with immunotherapy. Clearly, immunotherapy improves outcomes for patients. Saving immunotherapy to second line—we have approval for nivolumab and pembrolizumab as single-agent therapies between second- and third-line therapies. Saving plain immunotherapy for the second-line setting, to me, doesn’t make as much sense. A patient has symptoms. Their cancer can be rapidly progressive. I want to give them the first shot at goal up front—their best shot during their first shot. I think the paradigm of immunotherapy plus chemotherapy, when you first meet a patient, is the most appropriate in 2019 and beyond.

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