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Although there has been dramatic progress in the treatment landscape for metastatic melanoma over the past decade, many patients whose tumors harbor 

 mutations have not shared in the improved outcomes. There are no therapies designed to directly target this alteration, and some studies show a limited benefit from immunotherapy.

 mutations, which are detected in approximately 20% of cutaneous melanoma cases, are among the most frequently observed driver mutations in patients with the malignancy.

 Investigators are exploring several novel strategies to address the needs of this population, including the development of agents that target different nodes of the MAPK cell-signaling network that includes 

 alterations and is activated in nearly all cases of cutaneous melanoma.

Genentech is testing belvarafenib, a pan-RAF kinase inhibitor, in patients with 

 Novartis is evaluating LXH254, a RAF inhibitor that is highly selective for BRAF and CRAF, in patients with 

 Early-phase studies employing combinations that pair approved MEK inhibitors with other targeted agents also are under way 

Table. Ongoing Clinical Studies Targeting NRAS-Mutant Melanoma

 became the first oncogene described in melanoma after investigators analyzed DNA from melanoma cell lines.

 NRAS is a member of the RAS superfamily of guanosine triphosphate–binding proteins, which includes KRAS and HRAS. In melanoma, activated NRAS proteins leverage receptor tyrosine kinases to stimulate intracellular signaling in the MAPK pathway, which promotes cell proliferation and growth 

Figure. MAPK Signaling Network Drives Melanoma

NRAS mutations are the most frequently observed of the RAS isoforms in cutaneous melanoma. Whereas 

 mutations are detected in 2% and 1% of cutaneous melanomas, respectively, 

 mutations are found in 20%, most commonly in the exon 1 (G12 and G13 substitutions) and exon 2 link (Q61 substitution).

 mutations, however, have been overshadowed by 

 alterations. Nearly 40% of patients with melanoma have tumors harboring a 

 V600 aberrations as the most prevalent subtype, according to a whole-genome sequencing analysis by the Australian Melanoma Genome Project. That makes 

 the most frequently mutated gene, followed by 

Investigators have learned that patients with 

-mutated melanomas are generally older when they receive a diagnosis (> 55 years) with thicker tumors that are more likely to be located on the extremities and greater rates of mitosis than patients with 

 wild-type tumors. Although activating mutations of 

 typically exist independent of each other, both mutations are associated with aggressive melanoma and shorter survival compared with tumors that are wild-type for both aberrations.7 

 mutations, these alterations have proved more difficult to target than 

 mutations. The population of patients with 

 mutations is among those with melanoma in need of new therapeutic approaches, even amid the remarkable gains that have been made against the malignancy, experts say.

Since 2010, the melanoma field has witnessed a “golden decade,” according to Caroline Robert, MD, PhD, head of the dermatology unit at Gustave Roussy and codirector of the melanoma research unit at Paris-Sud University in Villejuif, France. Robert, a 2018 Giants of Cancer Care

 award winner in the melanoma category, reviewed progress in the treatment paradigm during an industry-sponsored symposium at the European Society for Medical Oncology (ESMO) 2021 Congress.

At the start of 2010, no systemic therapy had been shown to significantly extend survival in patients with metastatic melanoma, Robert said. The standard of care was chemotherapy with dacarbazine, which demonstrated a median overall survival (OS) of 231 days or 7.6 months, she noted. Today, the paradigm includes options for the adjuvant setting as well as immune checkpoint inhibitor (ICI) and targeted therapy for metastatic disease.

The progress that has been made is evident in recent long-term analyses of pivotal clinical trial data. The median OS ranged from 22.5 months to 33.6 months for patients with advanced melanoma with 

 V600 mutations treated with combination regimens of BRAF and MEK inhibitors, according to 5-year trial data. For patients with advanced melanoma who receive ICI therapy, the median OS reached 38.7 months with single-agent pembrolizumab (Keytruda), a PD-1 inhibitor, in a 5-year follow-up analysis of pooled data from the phase 3 KEYNOTE-006 trial (NCT01866319).

Meanwhile, patients with previously untreated advanced melanoma who received a combination of nivolumab (Opdivo), a PD-1 inhibitor, plus ipilimumab (Yervoy), a CTLA-4 inhibitor, achieved a median OS of 72.1 months in the phase 3 CheckMate 067 trial (NCT01844505), with 50% of the patients surviving 5 years, according to 6.5-year follow-up data.

 That outcome is nearly 10 times longer than the median OS was with dacarbazine, Robert noted. “This is huge, a huge improvement,” she said.

Nevertheless, Robert said, “it also means there are 50% of patients who have died of their melanoma in these 5 years and now it is for these patients that we have to work and understand how to optimize our treatments.”

Robert said there are several groups of patients not achieving long-term survival in the evolving melanoma landscape. These include patients who develop primary or acquired resistance to therapy, are unable to tolerate or receive current therapies, have high lactate dehydrogenase levels or a high disease burden, have brain and/or liver metastases, and Robert said there are several groups of patients not achieving long-term survival in the evolving melanoma landscape. These include patients who develop primary or acquired resistance to therapy, are unable to tolerate or receive current therapies, have high lactate dehydrogenase levels or a high disease burden, have brain and/or liver metastases, and have other melanoma subtypes such as mucosal melanoma.

Although targeted therapy and ICI therapy are twin pillars of the melanoma treatment paradigm, the National Comprehensive Cancer Network (NCCN) guidelines panel considers recommended ICI options as appropriate first-line systemic therapy for patients with distant metastatic or unresectable melanoma regardless of 

 mutation status. Preferred ICI regimens are single-agent nivolumab or pembrolizumab or the combination of ipilimumab plus nivolumab.

 V600 mutations, 3 regimens combining BRAF and MEK inhibitors also are category 1 choices: dabrafenib (Tafinlar) plus trametinib (Mekinist), vemurafenib (Zelboraf) plus cobimetinib (Cotellic), and encorafenib (Braftovi) plus binimetinib (Mektovi).

However, there is evidence that ICI therapy is not similarly effective across molecular subtypes. Patients with 

 V600 wild-type tumors represent a significant population with unmet needs, including those who receive ICI therapy in the front line, Matteo C. Carlino, MBBS, FRACP, PhD, said during a presentation at the 2021 American Society of Clinical Oncology Annual Meeting.

 Carlino is a medical oncologist at Westmead Hospital, Blacktown Hospital, and the Melanoma Institute Australia and a clinical associate professor at Sydney Medical School, University of Sydney.

In the broad category of patients without 

 mutations, ICI therapy outcomes are less beneficial than for those with 

 V600–mutated malignancy, Carlino said. In CheckMate 067, outcomes were worse for patients without 

 mutations. At 5 years, the OS rates for patients with 

 wild-type tumors were 60% vs 48%, respectively, for those who received the combination of nivolumab plus ipilimumab, 46% vs 43% for participants in the single-agent nivolumab arm, and 30% vs 25% in the ipilimumab-monotherapy group. Progression-free survival (PFS) rates and median OS also were higher for patients with 

 wild-type subgroup, approximately two-thirds of patients have progressed by 5 years and over 50% of patients have died in that time frame,” Carlino said. “As such there’s a significant patient population of 

 wild-type patients who require further treatment beyond an anti–PD-1 agent alone or in combination with ipilimumab.”

 mutations, clinical trial findings are more difficult to interpret. “There [are] conflicting data regarding the prognostic impact of 

 mutations, with some studies showing no impact, other studies saying [patients with] 

 mutations have a poorer survival, and there [are] some data to suggest there is a higher likelihood of response to immune checkpoint inhibition with 

Findings from the pivotal trials that led to FDA approval of ICI therapies did not specify outcomes for patients with 

 mutations, and much of what is known about the impact for this population comes from retrospective analyses, according to melanoma specialists from Vall d’Hebron Institute of Oncology in Barcelona, Spain. In findings from 3 ICI studies, patients with NRAS mutations had a lower rate of median OS in 1 study than participants with NRAS wild-type tumors (21 vs 33 months; 

 = .034), a higher rate in another (19.5 vs 15.2 months; 

 = .51), and no significant difference in the third study (32 vs 27 months; 

Investigators searching for new strategies for patients in underserved subgroups are focusing on the MAPK pathway, as 98% of cases in the Australian genomic study had at least 1 mutation in the network, Carlino noted. For 

-mutated tumors, some progress has been made with inhibiting MEK, another node in the pathway. However, MEK inhibition has shown limited efficacy as monotherapy, and combinations pairing these agents with CDK4/6 inhibitors, pan-RAF inhibitors, or PI3K inhibitors are being studied.

One MEK inhibitor that has shown positive results as a single agent is binimetinib, which demonstrated an improvement in PFS compared with dacarbazine for patients with 

-mutated melanoma. Binimetinib has been incorporated into the NCCN guidelines as a category 2B option for patients with this alteration who have progressed after prior ICI therapy.

In the phase 3 NEMO trial (NCT01763164), 402 patients with unresectable stage IIIC or stage IV 

-mutated melanoma who were either previously untreated or had progressed after prior immunotherapy were randomized 2:1 to receive either binimetinib at 45 mg orally twice daily or dacarbazine at 1000 mg/m2 intravenously every 3 weeks.

After a median follow-up of 1.7 months, the median PFS was 2.8 months (95% CI, 2.8-3.6) for those treated with binimetinib (n = 269) compared with 1.5 months (95% CI, 1.5-1.7) for participants given dacarbazine (n = 133), which translated into a statistically significant advantage for the targeted agent (HR, 0.62; 95% CI, 0.47-0.80; 1-sided 

 < .001). The overall response rate (ORR) was 15% (95% CI, 11%-20%) with binimetinib compared with 7% (95% CI, 3%-13%) with dacarbazine.

The benefit with binimetinib was more pronounced for participants who received previous immunotherapy. In this group, the median PFS with binimetinib was 5.5 months (95% CI, 2.8-7.6) compared with 1.6 months (95% CI, 1.5-2.8) for those who had dacarbazine. Moreover, the confirmed ORR was 16% among 57 patients in the binimetinib group compared with 4% among 28 patients in the dacarbazine arm.

Binimetinib also demonstrated an advantage in OS, a secondary end point of the trial, but not a statistically significant improvement. After a median follow-up of 9.2 months, the median OS in the binimetinib group was 11.0 months (95% CI, 8.9-13.6) compared with 10.1 months (95% CI, 7.0-16.5) in the dacarbazine cohort (HR, 1.00; 95% CI, 0.75-1.33; 1-sided 

NEMO, which was launched in 2013, was the largest study conducted in patients with 

-mutated melanoma at the time the f indings were published in Lancet Oncology in 2017, investigators said. However, Carlino said the study was conceived before PD-1 inhibitors were widely available. “There was a suggestion of a greater activity in patients with prior immunotherapy, but really this needs to be interpreted cautiously given the minority of patients who had prior immunotherapy,” Carlino said.

Investigators also tested binimetinib in combination with ribociclib (Kisqali), a CDK4/6 inhibitor that is FDA approved in combination with endocrine therapy to treat patients with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer.

 In a dose-expansion portion of a phase 1/2 study (NCT01781572), the combination resulted in an ORR of 19.5%, all partial responses, and a 51.2% stable disease rate in 41 patients with advanced or metastatic 

-mutant melanoma. The PFS was 3.7 months (95% CI, 3.5-5.6).

One emerging strategy for attacking NRASmutated melanoma is targeting RAF, one of the kinases in the MAPK pathway, in combination with other therapies. Genentech is collaborating with Hanmi Pharmaceutical Co Ltd, a company based in Seoul, South Korea, to develop belvarafenib, a pan-RAF inhibitor also known as HM95573, GDC-5573, and RG6185.

Belvarafenib monotherapy generated an unconfirmed best overall response in 4 of 9 patients (44.4%) patients with 

-mutant melanoma treated during a multicohort phase 1 dose-escalation study (NCT02405065) in advanced solid tumors. The median PFS among these patients was 24.9 weeks (95% CI, 4.8-84.0) with a median duration of response of 17.8 weeks (95% CI, 3.3-37.3). In a dose-expansion study (NCT03118817), 2 of 10 patients (20.0%) with NRAS-mutant melanoma reached a best overall response.

In ongoing research, the combination of belvarafenib plus cobimetinib, a MEK inhibitor, is being tested in patients with 

-mutated melanoma as part of an expansion cohort of a phase 1 study (NCT03284502) in locally advanced or metastatic solid tumors that have not responded to prior therapies or do not have standard treatment options. Other cohorts of this study focus on patients with 

In another phase 1 study (NCT04835805), belvarafenib is being evaluated as monotherapy and in combination with either cobimetinib or cobimetinib plus atezolizumab (Tecentriq), a PD-L1 inhibitor, in patients with 

-mutant advanced melanoma who have received prior anti–PD-1/ PD-L1 ICI therapy.

Results of preclinical studies in mouse models show that LXH254 strongly inhibits 2 members of the RAF family, BRAF and CRAF, but has limited activity against a third member, ARAF. Investigators theorize that LXH254’s sparing of ARAF may improve tolerability in normal tissues and make the agent a good candidate for combination therapy targeting downstream effectors, including MEK, ERK, or CDK4/6.

In a first-in-human phase 1 study (NCT02607813), LXH254 monotherapy was tested across 9 dosing levels in 81 patients with advanced solid tumors harboring at least 1 MAPK pathway alteration. Overall, 2 patients with 

-mutant disease achieved confirmed partial responses and 34.6% of participants reached stable disease. The study included 8 participants with skin melanoma but results for this cohort were not reported separately.

LXH254 is being evaluated in combination with LTT462, an ERK1/2 inhibitor; trametinib; or ribociclib in patients with previously treated unresectable or metastatic melanoma harboring 

 mutations in a phase 2 study (NCT04417621). Investigators aim to recruit 320 participants. 

 and other emerging targetable mutations in melanoma. Presented at: 2021 American Society of Clinical Oncology Annual Meeting; June 4-8, 2021; virtual. https://bit.ly/3F3Ykyc 

Robert C, Long G, Mohr P. Shaping tomorrow today: what does the future hold for melanoma? Presented at: European Society for Medical Oncology 2021 Industry Satellite Symposium; September 21, 2021; virtual. 

Garcia-Alvarez A, Ortiz C, Muñoz-Couselo E. Current perspectives and novel strategies of 

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Wood K, Luke J. The biology and therapeutic approach to BRAF mutant cutaneous melanoma. 

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Monaco KA, Delach S, Yuan J, et al. LXH254, a potent and selective ARAF-sparing inhibitor of BRAF and CRAF for the treatment of MAPK-driven tumors. 

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Albino AP, Le Strange R, Oliff AI, Furth ME, Old LJ. Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity? 

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Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

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Dummer R, Schadendorf D, Ascierto PA, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. 

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A phase Ib/II study of LEE011 in combination with MEK162 in patients with NRAS mutant melanoma. ClinicalTrials.gov. Updated December 7, 2020. Accessed September 28, 2021. 

https://clinicaltrials.gov/ct2/show/results/NCT01781572?view=results

Hanmi Pharmaceutical enters into an exclusive license agreement with Genentech for a novel oral RAF inhibitor. News release. Hanmi Pharmaceutical Co Ltd. September 29, 2016. Accessed September 29, 2021. 

Janku F, Iyer G, Spreafico A, et al. A phase I study of LXH254 in patients (pts) with advanced solid tumors harboring MAPK pathway alterations. 

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Articles

Although there has been dramatic progress in the treatment landscape for metastatic melanoma over the past decade, many patients whose tumors harbor  NRAS mutations have not shared in the improved outcomes. 

New Strategies Are Needed for Patients With NRAS-Mutant Melanoma

Triple-negative breast cancer (TNBC) is a biologically complex subtype characterized by an aggressive nature and heterogeneity. Standard chemotherapy has historically been the mainstay of treatment for patients with diagnoses of early-stage TNBC, but there remains an unmet need to identify novel therapies that improve outcomes and, equally important, to discern which patients may benefit from a given treatment.

The anti–PD-1 monoclonal antibody pembrolizumab (Keytruda) has shown impressive antitumor activity in the metastatic and curative settings for patients with TNBC. In the phase 3 KEYNOTE-355 trial (NCT02819518), the addition of pembrolizumab to chemotherapy significantly improved progression-free survival (PFS) vs chemotherapy alone among patients with previously untreated locally advanced inoperable or metastatic TNBC and combined positive score of at least 10. Specifically, the median PFS was 9.7 months with pembrolizumab/chemotherapy vs 5.6 months with placebo/chemotherapy (HR, 0.65; 95% CI, 0.490.86; 

In the curative space, neoadjuvant systemic therapy is favored for patients with early TNBC—specifically for tumors that are larger than 2 cm or with nodal involvement—and may be considered for smaller tumors in certain cases. Potential benefits of neoadjuvant chemotherapy include goal of downstaging the primary tumor and/or axilla to allow more surgical options (ie, breast-conserving surgery vs mastectomy) and assessment of the biology of the cancer via chemotherapy response, which can have prognostic and therapeutic implications. In I-SPY2 (NCT01042379), a phase 2 adaptively randomized platform trial for high-risk, stage II/ III breast cancer evaluating multiple investigational arms in different subtypes in parallel fashion, the addition of pembrolizumab to neoadjuvant chemotherapy (taxane-based and anthracycline-based) more than doubled the pathologic complete response (pCR) rate in hormone receptor–positive/HER2-negative and triple- negative subtypes.

Investigators of the phase 3 KEYNOTE-522 trial (NCT03036488) evaluated the role of pembrolizumab added to chemotherapy for high-risk (stage II/III) TNBC in the neoadjuvant setting. The chemotherapy backbone consisted of paclitaxel/carboplatin followed by anthracycline (doxorubicin or epirubicin)/cyclophosphamide. After surgery, patients received adjuvant pembrolizumab (n = 784) or placebo (n = 390) every 3 weeks for up to 9 cycles. The pCR rate was 64.8% in the pembrolizumab/chemotherapy group vs 51.2% in the placebo/chemotherapy group, yielding an absolute benefit of 13.6% (95% CI, 5.4-21.8; P < .001).

At median follow-up of 39.0 months, 84.5% of patients who received pembrolizumab plus chemotherapy were alive and had not experienced an event-free survival (EFS) event vs 76.8% of those who received chemotherapy alone (HR, 0.63; 95% CI, 0.48-0.82; P = .00031).

 These updated findings regarding EFS benefit led to the FDA approval of pembrolizumab plus chemotherapy for highrisk early-stage TNBC as neoadjuvant therapy, followed by pembrolizumab as single-agent in the adjuvant setting.

 Notably, pembrolizumab benefit was seen irrespective of PD-L1 status.

Olaparib Proves Effective in Mutant Disease

 mutations are more prone to double-strand DNA breaks that cannot be repaired because of a defective homologous recombination repair pathway. PARP inhibition leads to synthetic lethality and cancer cell apoptosis. Two PARP inhibitors, olaparib (Lynparza) and talazoparib (Talzenna), have demonstrated PFS benefit compared with chemotherapy in patients with germline 

 mutations and HER2-negative metastatic breast cancer, in the OlympiAD (NCT02000622) and EMBRACA (NCT01945775) trials, respectively.

The phase 3 OlympiA trial (NCT02032823) was designed to explore the role of olaparib in the adjuvant setting among patients with HER2-negative early breast cancer with 

 germline mutations after receipt of neoadjuvant or adjuvant chemotherapy. Patients with TNBC were required to have a primary tumor measuring at least 2 cm or node-positive disease if treated in the adjuvant setting, or presence of residual disease (no pCR) post neoadjuvant chemotherapy.

One year of adjuvant olaparib led to a statistically significant improvement in both invasive and distant disease-free survival (DFS), with absolute benefits of 8.8% and 7.1%, respectively (

). The 3-year invasive DFS rate was 85.9% in the olaparib group vs 77.1% in the placebo group (HR, 0.58; 95% CI, 0.41-0.82; 

 < .001). The 3-year distant DFS rate was 87.5% in the olaparib group vs 80.4% in the placebo group (HR, 0.57; 95% CI, 0.39-0.83; 

Residual Disease Post-Neoadjuvant Therapy

The presence of increasing amounts of resid-ual disease after neoadjuvant systemic therapy has been shown to correlate with inferior prognosis compared with those patients who achieve a pCR or have mini-mal residual cancer burden (RCB). Symmans et al investigated long-term prognosis in each breast cancer phenotype related to RCB post neoadjuvant chemotherapy.

 Among those with TNBC, good prognoses were seen for patients who achieved a pCR or RCB-I; outcomes were inferior for those with RCB-II or RCB-III (estimated 5-year relapse-free survival rates: pCR 94%, RCB-I 89%, RCB-II 62%, RCB-III 26%).

 Thus, efforts have been focused on developing strategies to improve outcomes for patients who have a less robust response to neoadjuvant therapy.

In the phase 3 CREATE-X trial (UMIN000000843), patients with HER2-negative breast cancer with residual disease after neoadjuvant chemotherapy (anthracy-cline, taxane, or both) were randomized to capecitabine for 6 to 8 cycles, or standard postsurgical management (control group). This study demonstrated DFS and OS bene-fit with the addition of capecitabine vs control in the TNBC subgroup. The 5-year DFS rates were 69.8% vs 56.1%, respectively (HR, 0.58); the 5-year OS rates were 78.8% vs 70.3%, respectively (HR, 0.52).

 As a result, adjuvant capecitabine became standard of care for patients with residual TNBC post neoadjuvant therapy.

The phase 3 ECOG-ACRIN EA1131 trial (NCT02445391) randomized 410 patients with stage II/III TNBC who had at least 1 cm of residual disease after completion of neoadjuvant therapy (taxane with or without anthracycline) to platinum-based chemo-therapy or capecitabine. After a median follow-up of 20 months, the 3-year invasive DFS rates were 42% with platinum and 49% with capecitabine (HR, 1.06) for patients with basal subtype TNBC. Furthermore, grade 3/4 toxicities were higher in the plati-num arm.

 This trial was therefore stopped early because of the improbability of demonstrating noninferiority.

The treatment of early-stage TNBC is evolving rapidly. Although these advances provide additional options for patients, they simultaneously create more questions for oncologists. Considerations include selection of patients for various therapies, how to sequence agents, and monitoring of adverse effects. As more experience is gained with these treatments and guidelines build on data and approvals, questions will gradually be answered, although new ones surely will arise as the early TNBC field continues to expand.

Cortes J, Cescon DW, Rugo HS, et al; KEYNOTE-355 Investiga-tors. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inopera-ble or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9

Nanda R, Liu MC, Yau C, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the on-going phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020;6(5):676-684. doi:10.1001/jamaoncol.2019.6650

Schmid P, Cortes J, Dent R, et al. KEYNOTE-522: phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC. Ann Oncol. 2021;32(9):P1198-P1200. doi:10.1016/j.annonc.2021.06.014

FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. FDA. Updated July 27, 2021. Accessed September 22, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembroli-zumab-high-risk-early-stage-triple-negative-breast-cancer

Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533. doi:10.1056/NEJMoa1706450. Published correction in N Engl J Med. 2017;377(17):1700. doi:10.1056/NEJMx170012

Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379(8):753-763. doi:10.1056/NEJMoa1802905

Tutt ANJ, Garber JE, Kaufman B, et al; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215

Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060. doi:10.1200/JCO.2015.63.1010

Masuda N, Lee SJ, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645

Mayer IA, Zhao F, Arteaga CL, et al. Randomized phase III postoperative trial of platinum-based chemotherapy versus capecitabine in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: ECOG-ACRIN EA1131. J Clin Oncol. 2021;39(23):2539-2551. doi:10.1200/JCO.21.00976

Partner Perspective

Standard  chemotherapy has historically been the mainstay of treatment for patients with diagnoses of early-stage TNBC, but there remains an unmet need to identify novel therapies that improve outcomes and, equally important, to discern which patients may benefit from a given treatment.  

A Dynamic Treatment Landscape Emerges for Early-Stage TNBC

Investigators look to boost systemic therapy options for patients with malignant pleural mesothelioma with the phase 3 DREAM3R trial (NCT04334759). The study, which was initiated March 17, 2021, will further examine the safety and efficacy of durvalumab (Imfinzi) in combination with the standard chemotherapy regimen of cisplatin and pemetrexed (CP) in adult patients with MPM and attempt to fill the long unmet need for additional treatment options for this population.

“When you block PDL-1, the idea is that the immune system can recognize foreignness within the tumor, particularly peptides and new antigens, [so that] it can then destroy the tumor cells,” explained Patrick Forde, MBBCh, director of the Thoracic Oncology Clinical Research Program and an associate professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, in an interview with 

®. “In other tumor types, including lung cancer, there has been shown to be synergy between chemotherapy and immunotherapy. Therefore, we believe that’s something [that] could potentially work well in mesothelioma as well.”

Initial Safety and Efficacy Data Spark Further Research 

Patrick Forde, MBBCh The addition of durvalumab to CP was previously evaluated in the single-arm, phase 2 DREAM trial (ACTRN12616001170415). The trial enrolled 55 adult patients with MPM across 9 sites in Australia. Eligible patients were those with histologically confirmed MPM considered unsuitable for cancer-directed surgery, and measurable disease per modified RECIST 1.0 previously untreated with systemic therapy.

Study participants received cisplatin 75 mg/m

, and durvalumab 1125 mg intravenously on day 1 of a 3-week schedule for a maximum of 6 cycles. Treatment with durvalumab continued for up to 12 months, and safety analyses included all patients who received at least 1 dose of any study drug. The primary end point of the trial was progression-free survival (PFS) at 6 months.

Eligible patients (n = 54) were followed for a median of 28.2 months (interquartile range, 26.5-30.2) and the PFS at 6 months was 57% (95% CI, 44%-70%). The most common adverse events (AEs) of grade 3/4 were neutropenia (13%), nausea (11%), and anemia (7%). Five patients died during the study treatment, but none of these deaths was attributed to the treatment.

Investigators also evaluated the combination in patients with MPM in the single arm, phase 2 PrE0505 trial (NCT02899195). PrE0505 enrolled 55 patients across 15 sites in the United States. Patients with unresectable MPM, no prior therapies, and an ECOG performance status of 0 or 1 were eligible for the trial. Most patients had epithelioid histology (74.5%) and the median age was 68 years (range, 35-83).

Patients were given durvalumab at a dose of 1120 mg plus pemetrexed 500 mg/ m

 every 3 weeks for 6 cycles until disease stabilization or a response, then patients were given 1120 mg of durvalumab every 3 weeks until disease progression for a maximum of 1 year. The primary end point of the study was overall survival (OS). Secondary end points included PFS, safety, and objective response rate.

Two systemic therapy options for MPM are approved by the FDA: CP and the immune checkpoint inhibitor (ICI) combination nivolumab (Opdivo) plus ipilimumab (Yervoy). The combination was approved on October 2, 2020, for the first-line treatment of adults with MPM that cannot be removed by surgery.

“Chemotherapy was first shown to have a survival benefit for MPM [in 2003]—that was cisplatin and pemetrexed as first-line treatment for patients with newly diagnosed MPM,” Forde said. “The [median] survival in that study was 12.1 months, and that was approximately a 2- to 3-month improvement over cisplatin alone. Then for approximately 16 years, there were no advances, no new studies showing benefit. [In 2021], we saw the publication of the [results of the] phase 3 CheckMate743 study [NCT02899299]

, which was a global study that randomized patients to either cisplatin and pemetrexed or ipilimumab and nivolumab combination immune checkpoint therapy.”

Forde noted that the greatest survival benefit was observed in patients with nonepithelioid MPM, a histological subtype associated with poor prognosis.5 “There was a very marked benefit, improving survival from 8 months for patients with chemotherapy alone to 18 months with the [immune checkpoint combination],” he said. Specifically, the median overall survival among the 74 patients with nonepithelioid disease who received the combination was 18.1 months (95% CI, 12.2-22.8) vs 8.8 months (95% CI, 7.4-10.2) among the 75 patients treated with chemotherapy alone (HR, 0.46; 95% CI, 0.31-0.68). In the epithelioid group, the 229 patients treated with the ICI combination had a median OS of 18.7 months (95% CI, 16.9-22.0) compared with 16.5 months (95% CI, 14.9-20.5) for the 227 patients who received chemotherapy alone (HR, 0.86; 95% CI, 0.69-1.08).

“We believe there’s still a role [for nivolumab plus ipilimumab] there for treatment innovations, particularly for those patients with epithelioid disease,” Forde said. “It’s great that we have a new option for patients with MPM [with] nivolumab and ipilimumab. However, it’s notable that the benefit [with that regimen] was predominantly in those patients with nonepithelioid disease, which [accounts for] approximately 20% to 25% of patients [with MPM]. Also, survival was quite similar between chemotherapy and combination immune checkpoint therapy for patients with epithelioid MPM.”

Investigators hypothesize that the DREAM3R trial may offer a benefit for all histologies of MPM.

DREAM3R is an open-label, randomized study that will enroll approximately 480 treatment-naïve patients with MPM in the United States, Australia, and New Zealand. Patients will be randomized 2:1 to receive durvalumab in addition to the standard treatment of CP or standard chemotherapy alone. Patients will be stratified by age (18-70 years vs older than 70 years), sex, histology (epithelioid vs nonepithelioid), and region (Australia/New Zealand vs United States).

Patients in the experimental arm will receive durvalumab at a dose of 1500 mg every 3 weeks, plus standard cisplatin 75 mg/m

 every 3 weeks for 4 to 6 cycles, followed by durvalumab 1500 mg every 4 weeks. Those in the control arm will receive standard chemotherapy alone at the same dose as the experimental group for 4 to 6 cycles followed by observation (

Treatment will continue in the experimental arm until disease progression, unacceptable toxicity, or patient withdrawal. Tumor and quality-of-life assessments will be performed at baseline then at weeks 6, 12, 18, 26, 34, 42, and 50, followed by every 12 weeks until disease progression. A pretreatment tumor tissue sample will be required, and blood samples will be taken on day 1 of cycles 2 and 3.

To be eligible for the study, patients be at least 18 years old with MPM of any histological type that is measurable by mRECIST 1.1. Eligible patients must have an ECOG performance status of 0 or 1; adequate bone marrow, kidney, and liver function; and a life expectancy of at least 12 weeks. Patients will be recruited over a period of 27 months and followed for another 24 months.

Patients will be excluded from the trial if they have any condition requiring systemic treatment with corticosteroids or other immunosuppressive agents. Patients who received a diagnosis based on cytology or fine needle aspiration only, contraindication for immune checkpoint inhibitors, or prior systemic anticancer therapy for MPM also will be ineligible.

The primary end point of the trial is overall survival. Secondary end points include progression-free survival, objective tumor response, and safety. Exploratory objectives will include the identification of biomarkers for response in tissue and serial blood samples, such as PD-L1 expression, human leukocyte antigen subtypes, tumor mutational burden, and validation of radiological measures of response and radiomic biomarkers. The estimated study completion date is December 2025.

“Particularly for patients with epithelioid histology, we see this [phase 3 trial] as having the potential to move the paradigm further,” Forde said. “If we can demonstrate a survival benefit from adding immunotherapy up front to chemotherapy, both of which are potentially effective therapies, especially for epithelioid disease, we could have a new option in the first-line setting. That’s something we’re hopeful to find from DREAM3R and from other ongoing studies.”

Investigators look to boost systemic therapy options for patients with malignant pleural mesothelioma with the phase 3 DREAM3R trial.

First-Line Durvalumab Aims to Add Additional Treatment Option in Malignant Pleural Mesothelioma

Since Charu Aggarwal, MD, MPH, helped conduct the first phase 1 trial of pembrolizumab (Keytruda) nearly a decade ago, she has been recognized as a pioneer in testing immunotherapy treatments for thoracic cancers. From this launchpad, her research focuses broadened to include liquid biopsies, expanding the knowledge bank of personalized care for patients.

Aggarwal is the Leslye M. Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania (UPenn) Perelman School of Medicine in Philadelphia. In her work at UPenn, Aggarwal conducts research in a variety of areas, particularly the development and validation of liquid biopsies designed not only for initial diagnosis, but also for the repeated evaluation of a treatment’s initial and ongoing efficacy.

“Dr Aggarwal has conducted some of the pioneering work in liquid biopsy research, work Howard “Jack” West, MD that has changed how we use liquid biopsies and increased our confidence in it as a routine tool,” Howard “Jack” West, MD, clinical executive director of AccessHope and associate clinical professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Duarte, California, said.

“She has also helped conduct and oversee some of the important retrospective database work that has shaped our ideas of optimal care for patients with 

 mutations, determining whether they should receive immunotherapy alone or immunotherapy with chemotherapy,” said West, who has worked with Aggarwal for many years and hosts a podcast with her.

Benjamin Levy, MD, associate professor at Johns Hopkins University School of Medicine and clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Baltimore, Maryland, echoed West’s praise for Aggarwal’s work in liquid biopsies.

“She has done some of the seminal work with liquid biopsies in advanced lung cancer,” he said. “Through her research, she has demonstrated that circulating tumor DNA [ctDNA] can be a very powerful tool in not only genotyping lung cancer patients, but also serving as a real-time surrogate or response in patients treated with targeted therapy and immunotherapy via longitudinal assessments with this platform.”

Levy described Aggarwal as incredibly persistent. “She doesn’t stop until the research question is answered,” he said. “When you combine that dedication with intelligence [and] ability to think out of the box and investigate ideas that others haven’t considered, you have a very successful researcher.”

 International Congress on Immunotherapies in Cancer

, which will take place as a hybrid, interactive event on Saturday, December 11 at the InterContinental New York Times Square.

The 1-day conference, hosted by Physicians’ Education Resource

), will provide a comprehensive review of clinical trial–derived and real-world data that are most relevant to the application of cancer immunotherapy. Topics of particular attention will be new developments in biomarkers, recent immunotherapy combinations, and strategies for mitigating adverse events (AEs).

Aggarwal and conference cochair Mario Sznol, MD—who leads the melanoma program and coleads the cancer immunotherapy program at Yale Cancer Center, in New Haven, Connecticut—have assembled a team of experts to discuss recent findings in a host of subjects:

Stratifying risk and predicting response to immunotherapeutic regimens in cancer management 

Correlating each immunotherapy’s mechanisms of action to its application in the treatment of malignancy 

Evaluating emerging data from clinical trials on the efficacy and safety of cancer immunotherapy regimens 

Implementing practical strategies for the immunotherapy management of solid and hematologic malignancies, along with the management of AEs

“There has been this wave of approvals in the past few years, starting with melanoma and lung cancer and moving to other tumor types,” Aggarwal said in an interview with 

. “At the same time, we are seeing approved uses for immunotherapy move from the metastatic setting to the neoadjuvant and adjuvant settings in diseases such as kidney cancer, lung cancer, and more. What I want the attendees to take out of this conference is practical information on how to apply chemotherapy or immunotherapy in the clinic, in the context of new clinical information and new clinical trials that have been presented at recent meetings.”

Although neither of her parents were doctors, Aggarwal decided that she would make medicine her life’s work when she was 5 years old. The decision to specialize in cancer research was made when she was pursuing her master’s degree and had the opportunity to work on bone marrow transplants. Aggarwal’s principal research interests are strategies for improving decisions that will tailor treatments for each individual patient with cancer.

For example, she was recently the senior author of an analysis of the association of 

 variant status and outcomes in patients who received immunotherapy alone vs those who received immunotherapy plus chemotherapy.

 The study compared outcomes among 1127 patients with advanced nonsquamous non–small cell lung cancer (NSCLC) with PD-L1 expression of 50% or greater, 573 of whom (50.8%) had 

-mutant disease and 554 of whom (49.2%) had 

-mutant disease, overall survival (OS) did not differ between those treated with immune checkpoint inhibitor (ICI) monotherapy and chemoimmunotherapy; the median OS was 21.1 vs 20.0 months, respectively (adjusted HR, 1.03; 95% CI, 0.75-1.40; 

 wild-type disease, those treated with ICI monotherapy had worse survival vs those treated with chemoimmunotherapy, although the difference was not statistically significant (median OS, 13.6 vs 19.3 months, respectively; adjusted HR, 1.19; 95% CI, 0.89-1.58; 

Since Charu Aggarwal, MD, MPH, helped conduct the first phase 1 trial of pembrolizumab nearly a decade ago, she has been recognized as a pioneer in testing immunotherapy treatments for thoracic cancers. 

Vol. 22/No. 20 | Oncology Live®

New Strategies Are Needed for Patients With NRAS-Mutant Melanoma

A Dynamic Treatment Landscape Emerges for Early-Stage TNBC

First-Line Durvalumab Aims to Add Additional Treatment Option in Malignant Pleural Mesothelioma

Investigators Prepare for the Next Wave of Immunotherapy Advances

Tisotumab Vedotin Displays Efficacy, Tolerability in Cervical Cancer

Cemiplimab Expands Treatment Portfolio for Patients with Basal Cell Carcinoma

A New Era of Precision Medicine Takes Shape in Prostate Cancer

The Challenging Future of the FDA in the Cancer Arena