PD-L1 Inhibitors Plus Platinum Chemotherapy Demonstrates Favorable Data in ES-SCLC

Ticiana Leal, MD, the director of the Thoracic Oncology Program at the University of Wisconsin Carbone Cancer Center in Madison, WI, explained her approach to treating a patient with extensive-stage small cell lung cancer (ES-SCLC), during a Targeted Oncology Case-Based Roundtable event.

Targeted Oncology™: What would be your approach toward treating this patient at this point?

LEAL: Based on the NCCN [National Comprehensive Cancer Network] guidelines, there are 3 preferred treatment options for ES-SCLC: carboplatin [Paraplatin], etoposide [VePesid], and atezolizumab [Tecentriq], followed by atezolizumab maintenance; carboplatin, etoposide, and durvalumab [Imfinzi], followed by durvalumab maintenance; and cisplatin [Platinol], etoposide, and durvalumab, followed by durvalumab maintenance. 1 The standard is 4 cycles, with some patients receiving up to 6 cycles based on response and tolerability after 4 cycles.

There are some additional options, including using a platinum-based drug [carboplatin or cisplatin] and etoposide [EP] without immunotherapy, and, in certain circumstances, using a platinum regimen in combination with irinotecan [Camptosar].

What data support the addition of atezolizumab to EP chemotherapy for a patient like the one discussed in the case?

The IMpower133 trial [NCT02763579] looked at frontline patients with ES-SCLC, randomized 1:1 to atezolizumab, a PD-L1 inhibitor, in combination with EP for 4 cycles, followed by maintenance with atezolizumab until progression versus EP in combination with placebo, followed by maintenance with placebo.2 This was a double-blind study and the co-primary end points were overall survival [OS] and investigator assessed progression-free survival [PFS], and the secondary end points were the objective response rate, duration of response, and safety.

At the initial report, with a median follow-up of 13.9 months, there was a modest OS improvement, with a median OS of 12.3 months [with atezolizumab] versus 10.3 months [with placebo], but importantly, a hazard ratio [HR] of 0.7, with a 1-year OS of 51.7% versus 38.2%. Also, importantly, a PFS improvement was seen, with a 1-year PFS rate of 12.6% versus 5.4% with an HR of 0.77.

With further follow-up [of 22.9 months], this benefit was maintained at the 18-month OS landmark analysis.³

There was a 34% improvement versus 21% with an HR of 0.76. Although the difference in the median OS period [12.3 vs 10.3 months] doesn’t look very impressive, it is more meaningful to look at the global OS difference of 34% versus 21%. These results, together with the results from other trials such as CASPIAN [NCT03043872]^4-6 and KEYNOTE-604 [NCT03066778],⁷ show that there is a continued meaningful benefit over time of adding immunotherapy to chemotherapy. The benefit is not the same as with non–small cell lung cancer, but there is an incremental benefit for patients with SCLC, which is a gain.

In terms of the 2-year OS rate, most subgroups did benefit from the addition of atezolizumab to chemotherapy, including those with liver metastasis.³ There was no significant difference in terms of using blood TMB [tumor mutational burden] as a predictive biomarker [cutoff points of 10 or greater and 16 or greater]. Similarly, PD-L1 tissue level was also not predictive of the benefit of using atezolizumab in combination with chemotherapy [data not shown]. Therefore, this is a regimen that benefits the allcomer population.

The objective response rate was 60.2% for the atezolizumab group versus 64.4% for the placebo group.2 The median duration of response was slightly higher for the atezolizumab plus chemotherapy group, 4.2 versus 3.9 months,2 the ongoing response at the data cutoff was 14.9 versus 5.4 months,2 and the ongoing response at the 2-year follow-up was 9.1% versus 2.3%.3 Therefore, the addition of immunotherapy to chemotherapy increased the median duration of response.

A lot of the AEs [adverse effects] reported are due to the chemotherapy portion of the regimen,2 specifically, the myelosuppression associated with chemotherapy. The rate of immunotherapy-related AEs with atezolizumab was about 39% versus 24% with placebo. Since this was a double-blind placebo-controlled trial, the main immune-related AEs reported were rashes and hypothyroidism. The number of treatment-related deaths was very low and was balanced between the 2 arms at 1.5% for both.

What data support the addition of durvalumab to EP chemotherapy for a patient like the one discussed in the case?

The CASPIAN trial [NCT03043872] had a similar study design, compared with the IMpower133, except that it had 3 arms, randomized 1:1:1, instead of 2.⁴ This study enrolled a treatment-naive population with ES-SCLC. The first arm consisted of durvalumab, another PD-L1 inhibitor, plus EP for 4 cycles, followed by maintenance with durvalumab. The control arm consisted of up to 6 cycles of EP, and optional PCI [prophylactic cranial irradiation]. The experimental arms did not receive PCI.

The third arm consisted of the addition of tremelimumab, a CTLA-4 inhibitor, to durvalumab and EP for 4 cycles followed by maintenance with durvalumab. The primary end point was OS and the secondary end points included PFS, overall response rates, safety and tolerability, as well as patient-reported outcomes.

As with the IMpower133 trial, the CASPIAN trial showed a positive benefit of the addition of durvalumab to EP, with an improvement in the median OS of 12.9 months versus 10.5 months and an HR of 0.75.5 At the 24-month landmark analysis, the probability of OS was 22.2% versus 14.4%, with a median follow-up of 25 months.

Additionally, most of the subgroups also had a benefit in OS with the addition of durvalumab to EP.

From the way the study was set up, the median PFS did not have statistical power. Therefore, the PFS was not tested for statistical significance. However, the median PFS reported in the CASPIAN trial is similar to that of the IMpower133 trial. The probability of PFS is 11% in the durvalumab plus EP group versus 2.9% in the EP group.

The confirmed objective response rate was 67.9% for the durvalumab plus EP group versus 58% for the EP group. That is, the durvalumab plus EP response rate was a little bit higher despite the fact that in the EP arm they could use cisplatin and did use up to 6 cycles of EP versus 4 cycles in the durvalumab plus EP arm.⁶

The median duration of response was similar between the 2 arms. As expected, the proportion of patients in response was higher in the durvalumab plus EP arm [13.5%] versus the EP arm [3.9%]. The durvalumab plus tremelimumab plus EP did not meet the primary end point.⁵ Although there seemed to be a positive difference at first, the median OS was negative as there was increased toxicity. Therefore, this combination should not be used in clinical practice.

What do you think about the safety profile of durvalumab used in combination with EP?

According to the safety profile results, the addition of durvalumab to EP does not raise any concerns and seems to be a well-tolerated regimen. The most clear difference was in terms of immune-mediated events, where durvalumab plus EP had a 20% rate versus 2.6% for the EP arm.⁶ The difference between this study and others is that this was not a placebo-controlled, double-blind trial.

What are the differences between these 2 immune checkpoint inhibitors in the treatment of patients with ES-SCLC?

The differences are that with atezolizumab plus EP, carboplatin is the preferred platinum partner as that was the combination used in the clinical trials, whereas there is the option of using cisplatin with durvalumab plus EP. Although, in practice, there seems to be a preference for carboplatin. In terms of the dosage and administration, during the maintenance phase, atezolizumab can be given every 2, 3, or 4 weeks and durvalumab every 4 weeks. As for warnings and precautions, immune-related AEs are the most common and monitoring and patient education efforts are necessary. We have a pharmacy-led program to check in on patients and educate them on what to watch out for, which has helped us decrease the number of ER visits and the severity of immune-related AEs.

What would be your approach toward management and follow-up at this point?

These patients were excluded from the IMpower133 and CASPIAN trials. [Therefore, we do not have data to inform our decisions.] I’ve treated patients with paraneoplastic syndromes with immunotherapy combinations and they have done fine. I had a patient with a mild IgA nephropathy that was paraneoplastic, and she had stable renal function. Another patient had a neurologic paraneoplastic syndrome that was also relatively stable [subclinical], and she did OK. The decision may depend on how the patient is doing. These are difficult situations, but if a patient requires immunosuppression for the paraneoplastic syndrome, I would avoid treating them with immunotherapy. This is the standard approach for all patients that require immunosuppression.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer, version 2.2021. Accessed May 24, 2021. https://bit.ly/3bPxSeI}

_{2. Horn L, Mansfield AS, Szczęsna A, et al; IMpower133 Study Group. First- Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064}

_{3. Reck M, Liu SV, Mansfield AS, et al. IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann Oncol. 2019;30(suppl 5):v710-717. doi:10.1093/annonc/mdz264}

_{4. Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6}

_{5. Goldman JW, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum– etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S0140-2045(20)30539-8}

_{6. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab tremelimumab + platinum etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15);9002. doi:10.1200/JCO.2020.38.15_suppl.9002}

_{7. Rudin CM, Awad MM, Navarro A, et al; KEYNOTE-604 Investigators. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol. 2020;38(21):2369-2379. doi:10.1200/JCO.20.00793}