Robert L. Ferris, MD, PhD, Co-Physician Editor in Chief, <em>Targeted Therapies in Oncology</em>,<em> </em>discusses<em> </em>the<em> </em>evolving<em> </em>role of immunotherapy in melanoma and non–small cell lung cancer, where by it is now the dominant therapeutic approach in these diseases in progressively earlier lines of therapy.
Robert L. Ferris, MD, PhD
The emerging role of immunotherapy in melanoma and nonsmall cell lung cancer (NSCLC) has had a transformative effect on how these 2 cancer types have been managed over the past few years. A new paradigm has evolved where immunotherapy is now not only a new modality but is the dominant therapeutic approach in this disease in progressively earlier lines of therapy, including unresectable, resectable, and adjuvant therapy.
First, it should be recognized that for many patients up-front surgical therapy on the primary tumor with or without some nodal dissection, such as a sentinel lymph node biopsy, is standard of care. However, regional or distant relapse still may occur, and this has led to the institution of adjuvant therapies. In some situations, the unresectable disease status must be treated with systemic therapy to treat distant risk or distant clinically apparent disease. The history of innovative systemic therapies beyond chemotherapy for melanoma began with the interferon story in the 1990s. Historically, the use of interferon as an adjuvant was based on the fact that metastatic melanoma was and is a deadly disease, and early intervention could lead to improved long-term cure rates. Furthermore, the prognostic factors for assessing risk of recurrence have evolved but are now becoming more clearly defined. Interestingly, numerically, most deaths still originate in patients with intermediate (stage II/III) disease. Interferon alpha-2B was used in different dosages and frequencies in a series of clinical trials. However, controversy has surrounded the interferon story in the adjuvant setting for several reasons. First, only ECOG 1684 showed an overall survival (OS) advantage, whereas other trials showed only a recurrence-free survival (RFS) advantage.1In addition, which dosage and/or schedule to use was also unclear. This is more important in the setting of an agent like interferon, in which toxicity is significant, including potential constitutional symptoms, myelosuppression, hepatotoxicity, chronic fatigue, and other neurologic/psychologic effects. More recently, interferon has been superseded by newer agents.
Immune checkpoint inhibitors ipilimumab (Yervoy) and antiPD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) soon came on the scene, followed by atezolizumab (Tecentriq) and avelumab (Bavencio). Ipilimumab, a blocking anti–CTLA-4 antibody, was the first successful checkpoint inhibitor approved in metastatic melanoma or other aggressive malignancies. However, it is also the most toxic and has had to be dose reduced from the original approved 10 mg/kg down to 3 mg/kg, and even down to a dose of 1 mg/kg (with altered dosing) when used in combination with other agents.
The EORTC18071 trial demonstrated the superiority of ipilimumab in a randomized phase III study using the dose of 10 mg/kg for up to 3 years of maintenance after an induction phase, as compared to placebo. Although this drug was safe, there were some unexpected treatment-related adverse events (AEs) that were immune related, leading to death due to colitis, myocarditis, or neurologic problems.2The result is that ipilimumab was approved and works in the adjuvant phase, but it is too toxic and the dose was 3 times higher than that used for metastatic melanoma.
Next, antiPD-1 therapy was used and appeared to be better tolerated than ipilimumab in metastatic melanoma. Thus, the CheckMate 238 study compared nivolumab with an ipilimumab placebo versus ipilimumab with a nivolumab placebo. Nivolumab at 3 mg/kg was superior to ipilimumab at 10 mg/kg with a hazard ratio (HR) of 0.66 (P<.0001), constituting a median 30.8-month versus 24.1-month survival. There were no treatment-related deaths in the nivolumab group and data demonstrated that it had better tolerability than ipilimumab.3
The KEYNOTE-054 study demonstrated that adjuvant therapy as compared to placebo in over 1000 patients demonstrated a survival benefit for high-risk, stage III resected cutaneous melanoma with an HR of 0.57 and at 18 months and 18% better survival versus placebo.4Researchers have determined from these trials that antiPD-1 agents work in the adjuvant setting and are better than ipilimumab in terms of oncologic and toxicity profiles. These immunotherapy agents constitute a new standard of care in this setting.
Now combinations with the MAP kinase/MAPK inhibitors have been interesting given that 40% percent of patients with melanoma areBRAFpositive. In metastatic melanoma, targeted therapy with BRAF/MEK combinations work well and have been applied in the adjuvant setting. The COMBI-AD study randomized 870 patients based on a stratification ofBRAFmutated or wild type and stage. The combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) showed a dramatic greater-than-50% reduction in RFS (HR, 0.47), which was the primary endpoint of this study, as presented at the 2017 European Society of Medical Oncology Annual Congress.5Overall survival demonstrated a nearly 9% improvement in survival in patients treated with dabrafenib plus trametinib as compared to the placebo-treated patients. Pyrexia was one of the noted common AEs in the treatment arm. Thus, targeted therapy with BRAF/MEK combinations work in the adjuvant therapy setting with expected toxicity and this regimen has become a new standard of care forBRAF-mutated patients.
Putting it together, immunotherapy with antiPD-1 is effective in the adjuvant setting for high-risk patients with melanoma. BRAF/MEK targeted therapy is also effective for high-risk patients with aBRAF-mutant tumor. Now, sentinel nodepositive patients can be randomized to anti–PD-1 with or without dabrafenib plus trametinib. Such trials are bringing novel therapies into earlier lines of disease where cure rates may be higher. Yet controversies continue:
The evolution of immunotherapy into NSCLC, beyond recurrent and metastatic disease has been promising for this devastating and previously difficult-to-cure disease. Thus, efforts have emerged to integrate immunotherapy into the treatment of unresectable, stage III NSCLC. First, several questions arise, including who is resectable versus unresectable, often a source of controversy in the eye of the surgeon or multidisciplinary treatment team. Next, is whether neoadjuvant chemotherapy, chemoradiation, or adjuvant chemotherapy has been used or would be available to such a patient. Indeed, SEER database analyses demonstrate better outcomes with post-operative radiation, thus indicating that integration into multi-modality management is the current standard of care for any new immunotherapeutic.
Patients with stage IIIA NSCLC was enrolled in the intergroup trial 0139 which randomized patients to chemoradiation (45 Gy) followed by surgery to chemoradiation (61 Gy) alone. With an HR of 0.77, the lower-dose chemoradiation followed by surgery showed a statistically significant improvement in progression-free survival, but not OS (HR, 0.87).6Then, the SWOG 9504 trial tested the benefit of docetaxel after concurrent chemoradiation using cisplatin etoposide and 61 Gy, with consolidation using 3 cycles of docetaxel. The median survival time was 26 months with a 5-year survival rate of 29%.7
A further trial randomized to docetaxel at 75 mg/m2every 3 weeks for 3 cycles versus observation (7512 HOG Trial). Of 147 randomized patients, there was no statistical difference between the observation or the docetaxel arm.8Using targeted therapy, the SWOG 0023 trial compared adjuvant gefitinib (Iressa) versus placebo after chemoradiation followed by docetaxel. Chemoradiation using platinum and VP-16 with 61 Gy of radiation consolidated with 3 cycles of docetaxel then led to a randomization of gefitinib (an EGFR tyrosine kinase inhibitor) versus placebo. Interestingly, OS was lower in the gefitinib-treated patients versus those treated with placebo (P= .01).9
In this setting, the PACIFIC trial was a phase III, randomized, double-blind, placebo controlled multicenter international study. Patients with stage IIIB, locally advanced unresectable NSCLC who had not progressed following definitive platinum-based concurrent chemoradiation were treated between 1 and 42 days post concurrent chemoradiation with either durvalumab (Imfinzi; 10 mg/kg for up to 12 months) or placebo. Of 983 patients, 713 underwent randomization. The trial was dramatically positive with the durvalumab-treated patients demonstrating significantly reduced disease progression or death with an HR of 0.52 (2-sidedP<.001).10In these patients, disease stage IIIA or IIIB appear to benefit equally, although nonsmokers seem to derive the greatest benefit. An additional subgroup that demonstrated benefit, as expected, was those with PD-L1 expression greater than 25%, the standard threshold for durvalumab trials.EGFR-mutated patients did perhaps worse thanEGFRnon-mutated patients. The overall HR for risk of death was substantially improved at 0.68 with a significantPvalue.11Durvalumab was very well tolerated with roughly 3% grade 3/4 AEs in both arms, including the placebo arm.
In summary, what is unresectable stage III is not completely defined in the field and could even shift as new data emerge. However, clearly there is reason for enthusiasm with the role of adjuvant immunotherapy given the failure and disappointment of other chemotherapeutic or targeted agents in this setting. The FDA approved durvalumab post-chemoradiation in this setting, and the tolerability of durvalumab after chemoradiation has been surprisingly good. Yet, cost may be an issue without enriching patients based on selected biomarkers.
Robert L. Ferris, MD, PhD, is the Co-Physician Editor in Chief, Targeted Therapies in Oncology and director of the Hillman Cancer Center,University of Pittsburgh Medical Center, in Pittsburgh, Pennsylvania.