Peter J Sciavolino, PhD

The landscape of treatment options for patients with advanced and/or metastatic melanoma continues to expand, with immunotherapies and targeted therapies, as well as combinations thereof, gaining approval in recent years. As such, it is becoming increasingly important to understand the patient-specific oncogenic drivers, as a means of selecting treatments. The current National Comprehensive Cancer Network (NCCN) guidance recognizes the importance of

testing (for patients with metastatic disease).

As clinical experience grows with new agents, combinations, and sequences of therapy, the use of molecular profiling in metastatic melanoma is likely to become an essential means of choosing among treatment options.

Patients with metastatic or unresectable melanoma are now candidates for first-line systemic therapy with antiPD-1 receptor antibodies (Category 1) as monotherapy (pembrolizumab and nivolumab), but targeted therapies are preferred if

mutated, in cases where an early response is clinically desirable.

Other options include the nivolumab/ipilimumab (antiCTLA-4) combination.

demonstrated that the use of nivolumab, an anti-PD-1 agent, either alone or in combination with ipilimumab, an antiCTLA-4 agent, significantly improved median progression-free survival (PFS) compared with ipilimumab alone.

Keith T. Flaherty, MD director of clinical research and of the Henri and Belinda Termeer Center for Targeted Therapies and at Massachusetts General Hospital Cancer Center, notes that a range of treatment options now exist for patients with

Current NCCN guidance recommends considering targeted therapies for patients with

-mutant melanoma with symptomatic disease, or who progress on immunotherapies.

Vemurafenib was the first targeted therapy to become available for patients with metastatic melanoma, and was shown to improve overall and progression-free survival (PFS) over conventional chemotherapy (dacarbazine), the standard of care at the time.

Vemurafenib is currently approved for use in patients with

-mutationpositive melanoma, as determined by an FDA-approved test (Cobas).

Subsequently, a second BRAF inhibitor dabrafenib, became available for use after it was shown to also improve PFS compared with dacarbazine.

Adverse events (AEs) associated with these BRAF-targeted therapies include skin toxicities, which were observed in a sizable proportion of patients.

It now appears that these toxicities stemmed from a paradoxical activation of the MAP kinase pathway by these agents, and these observations, in addition to the propensity to develop resistance to monotherapy, have more recently paved the way for their use in combination with MEK-directed agents in patients with

Recent phase III trials have established the clinical feasibility of using BRAF inhibitors and MEK inhibitors in combination.

One trial combined dabrafenib with the MEK inhibitor trametinib (compared with dabrafenib and placebo) in previously untreated patients with unresectable advanced melanoma harboring

The results showed significantly improved PFS (primary endpoint, HR = 0.75;

= .03), as well as response and overall survival (OS) for patients receiving the combination versus those receiving the single agent (

Notably, the incidence of cutaneous squamous cell carcinoma and cutaneous hyperkeratoses was lower with the combination, although the incidence of other AEs (eg, pyrexia 51% vs 28%) was higher.

In a similarly designed trial comparing vemurafenib combined with the MEK inhibitor cobimetinib with vemurafenib alone, the use of the BRAF/MEK combination therapy also resulted in significantly improved PFS (HR = 0.51;

<.001), response, and interim OS (Table 1), with a similar impact on skin toxicities.

Table 1:  Selected Efficacy and Safety Endpoints in Phase III Trials of BRAF/MEK Inhibitor Combinations

Dabrafenib/Trametinib vs Dabrafenib/Placebo

Vemurafenib/Cobimetinib vs Vemurafenib/Placebo

Articles

With the continuously expanding landscape of treatment options for advanced and/or metastatic melanoma, it is becoming increasingly important to understand the patient-specific oncogenic drivers as a means of selecting treatments.

BRAF Testing Important for Clinical Decision-Making in Metastatic Melanoma

Because it is noninvasive, this method may be used to re-assess evolving tumors without a repeat biopsy.

At the American Society of Clinical Oncology (ASCO) 2014 meeting, Morelli et al reported use of this technology to detect, in a single test, both somatic mutations and copy number alterations in patients with treatment-refractory metastatic colorectal cancer (mCRC).

They demonstrated the coexistence of multiple acquired somatic mutations and copy number alterations in patients with epidermal growth factor receptor (EGFR) antibody-refractory mCRC (

FIGURE 1. Gene copy number alterations detected using the Guardant360 system.

At the 2014 San Antonio Breast Cancer Symposium (SABCS), Austin et al reported genomic alterations over the course of disease in a patient with inflammatory breast cancer (IBC).

shows the evolution of genomic alterations in this patient, with 15 alterations detected after neoadjuvant therapy, 3 alterations detected after 3 months of adjuvant therapy, and no alterations detected at the end of adjuvant therapy. Notably, 4 months after completing adjuvant therapy, the patient showed a new mutation (before detectable clinical progression).

Targeted Oncology: asked 3 experts in tumor genomics to comment on the clinical potential and application of molecular tests such as Guardant360.

is director of the thoracic oncology program, professor, and senior advisor to the director of the University of California Davis Comprehensive Cancer Center. He is also the founding cochair for the National Cancer Institute (NCI) Investigational Drug Steering Committee, chair for the NCI Lung Correlative Science Committee, and chair of the Southwest Oncology Group (SWOG) Lung Committee.

Q: Why is genomic testing important in lung cancer?

Lung cancer is one of the most genomically complex cancers, and sorting out what is actually driving the patient&rsquo;s cancer, and what is an unrelated abnormality, or a comutation, is challenging. More and more we are into an algorithm, which requires periodic repeat tumor biopsies after every therapy, particularly in these oncogene-driven lung cancers. This is also challenging, because many patients may have a new metastasis in a hard-to-biopsy site (eg, brain, bone), and such biopsies are invasive and costly. Use of cfDNA testing allows you to do repeat testing on a sequential basisevery 2 months if you like&mdash;to see if you can detect these new potential drivers and anticipate them ahead of time.

Q: How are these testing platforms (eg, Guardant360) being used in lung cancer clinical practice, and what do you think will be their potential use in the future?

About a year and a half ago, we were doing single-gene and multiplex testing in lung cancer, and we had predicted we would be moving into tissue-based NGS. Here it is now, just 16 months later, and [it&rsquo;s] now routine. Moreover, the next future, plasma-based testing is also here. So right now, the percentage of patients getting this type of testing could be perhaps 1%, and most of that is people doing research, but ask the same question 1 year from nowI think it&rsquo;s going to be quite different.

Q: Are any large-scale initiatives now using this technology for lung cancers?

The SWOG has a large clinical trial about to begin (S1403) in patients with untreated, newly diagnosed, stage 4, EGFR-mutated lung cancer to examine the impact of dual EGFR inhibition. This trial will employ a serial plasma DNA (mutational) analysis, in an effort to see if we can predict early recurrence, and the likelihood of the acquired resistance mechanism.

is an associate adjunct professor and director of molecular pharmacology in the department of internal medicine and the division of hematology and oncology at the UC Davis Comprehensive Cancer Center.

Q: What are your perspectives on the performance and clinical utility of tests such as Guardant360 in oncology?

This technology can serve as a substitute when a biopsy is not possible. We&rsquo;re not clear as yet if it will be as routinely predictive as having a piece of tumor tissue, but it certainly can be very informative. Secondly, it can be very useful for following adaptive changes over the course of treatment, for instance, early detection of the emergence of resistance mutations. Also, the ability of this technology to observe tumor DNA copy number abnormalities in plasma is very forward looking.

Q: Can you comment on the performance of this technology relative to tissue biopsy in addressing issues like intratumor heterogeneity?

It&rsquo;s not clear whether, even in plasma, you will be able to pick up every genetic variation out there, nor would you be able to state definitively that mutation X and mutation Y are occurring in the same tumor cells. However, it is reasonable to speculate that the most aggressive forms of the tumor, even if they represent only a small portion of the overall tumor burdenfor instance, metastatic variants&mdash;would be leaking detectable DNA into the peripheral circulation, and therefore would be highly therapeutically informative, possibly more so than a biopsy of the primary lesion.

Q: How might more comprehensive testing across multiple tumor types be beneficial to expand the use of targeted therapies in cancer?

A number of cancer types are at the forefront of targeted, precision therapy, including lung cancer. It is not entirely clear whether this is due to unique properties of those cancers, or just a failure to identify similar oncogenic drivers in other tumor types. So once we analyze all cancer types using these systematic screens, we may identify, at least in small patient subsets, some tumor dependencies that would make themselves amenable to targeted therapies. This will be particularly important for rare tumors that are not as well studied as the major forms.

is an assistant professor of medicine in the department of internal medicine and the division of hematology and oncology at the UC Davis Comprehensive Cancer Center.

Q: How does biopsy-free genomic profiling using cfDNA offer an advantage over tissue-based analyses?

Tumor biopsies are potentially limited by a sampling bias. We know from studies of multiple tumor types that there can be incredible heterogeneity within a single patient&rsquo;s tumor. This heterogeneity exists within an individual lesion as well as between different metastatic sites and the primary tumor. Circulating cfDNA may provide a more representative sample of tumor DNA, although this is admittedly based on the assumption that tumor DNA is shed from tumors in a randomly distributed fashion. Tumor biopsies also provide a snapshot in time, and genomic profiling of a tumor prior to treatment will likely be different after multiple lines of treatment. Biopsy-free genomic profiling, on the other hand, can be done with a simple blood test and is therefore significantly more amenable to serial testing to provide up-to-date genomic profiling data, and also makes it possible to obtain information in cases where tissue access is limited due to location or tumor yield (eg, pancreatic cancer).

Q: What are some of the limitations of these types of analyses?

There are many limitations to applying the knowledge from genomic profiling to treatment decisions. Some of these limitations apply to all methods of genomic profiling, regardless of whether it is through direct analysis of tumor tissue or isolation of cell-free circulating DNA. These limitations include the potential for finding many genomic changes that are not actionable, in terms of an available therapy that is either approved or in development. There may also be an available therapy, but not for the specific disease application, thus limiting its true availability. Even if a drug is available, there may not always be a correlation between the identified genomic abnormality and response to the drug.

The greatest utility in genomic profiling is to provide potentially useful information that can guide patients toward clinical trials. In patients with disease refractory to standard treatments (eg, in mCRC), biopsy-free assays provide a mechanism to obtain genomic profiling of a patient&rsquo;s tumor at the time of progression, as opposed to analyzing the original tumor biopsy or resection specimen, which may no longer be relevant after multiple lines of treatment.

Q: How might biopsy-free genomic profiling using cfDNA be important in guiding treatment for patients with GI cancers (eg, mCRC)?

We are approaching a point where our understanding of tumor biology, targeted therapies, and associated resistance mechanisms, and rapid drug development will be primed for widespread use of genomic profiling. Biopsy-free genomic profiling has the potential to significantly augment the patient population that can be tested.

Talasaz AA, Mortimer S, Schiller B, et al. Comprehensive profiling of cancer in real-time by digital sequencing of cell-free DNA from 520 patients with metastatic solid tumors and its clinical application. Poster presentation at EORTC.

Morelli MP, Overman M, Vilar-Sanchez E, et al. High frequency of concurrent gene mutations and copy number alterations in circulating cell-free DNA (cfDNA) from refractory metastatic CRC patients. ASCO 2014.

Austin L, Fortina P, Sebisanovic D, et al. Circulating tumor DNA (ctDNA) provides molecular monitoring for inflammatory breast cancer (IBC). San Antonio Breast Cancer Symposium.

Guardant360 is a highly sensitive digital sequencing system that requires only a 10 mL blood sample, and allows for simultaneous assessment of more than 60 actionable genes in circulating, cell-free DNA.

Three Experts Weigh In on Plasma-Based Molecular Profiling in Oncology

Advances in our understanding of critical immunomodulatory checkpoints, such as the cytotoxic T-lymphocyte antigen 4 (CTLA-4), have led to some recent notable successes in the immunotherapy of cancer.

An example is ipilimumab, a humanized monoclonal antibody directed against CTLA-4, which has been shown to significantly prolong survival when used as monotherapy in patients with advanced melanoma.

Nivolumab, another checkpoint inhibitor, which blocks the programmed death receptor 1 (PD-1) on activated T-cells, is also under investigation as an immunotherapy in cancer.

Another successful immunotherapy is sipuleucel-T; this immunotherapy entails patient-derived peripheral blood mononuclear cells and antigen-presenting cells, which have been activated ex vivo by prostatic acid phosphatase, and the immune activator granulocyte-macrophage colony-stimulating factor (GM-CSF).

This treatment has prolonged survival in men with metastatic castration-resistant prostate cancer (mCRPC).

In a recent panel discussion, Roy S. Herbst, MD, PhD, from the Yale Cancer Center, noted the potential for immunotherapies such as nivolumab to be used in combination with targeted therapies.

Gregory A. Daniels, MD, PhD, on Combining Immunotherapies

Daniels is a professor of medicine at University of California, San Diego.

&ldquo;We have an agent [nivolumab] that&rsquo;s going to become a backbone now for combination with some of the other targeted therapies that we use,&rdquo; Herbst predicted.

Discussing the rationale for immunotherapy combinations in non-small cell lung cancer (NSCLC), Karen L Reckamp, MD, MS, at City of Hope and Beckman Research Institute, in Southern California, said that &ldquo;harnessing the immune system is not just about the tumor cell&hellip; it&rsquo;s about the microenvironment and what&rsquo;s happening there, and we know that the microenvironment promotes metastatic disease, and progression, and so blocking some of those things may be attacking a part of the cancer we&rsquo;ve been ignoring.&rdquo;

A phase III study has investigated the safety and efficacy of dacarbazine, a standard chemotherapy treatment for advanced melanoma, in combination with ipilimumab,  compared with dacarbazine alone.

The results showed that the ipilimumab combination was significantly better than dacarbazine alone in prolonging overall survival (OS), with a hazard ratio (HR) for death of 0.72 (

<.001), and the benefit was observed for the combination across all of the subgroups examined.

The disease control rate (defined as complete [CR] or partial response [PR] or stable disease) did not differ significantly between the combination and the dacarbazine-alone groups (33.2% vs 30.2%;

=.41); however, the median duration of response (among those with CR or PR) was 19.3 months and 8.1 months, respectively (

=.03), indicating durable objective responses achieved with the ipilimumab combination. There were significantly more grade 3/4 adverse events (AEs) in the combination arm (56.3% vs 27.5%;

<.001). Although AEs were largely as expected with either therapy, elevated liver function test results were identified  more frequently with the combination.

Because they have distinct mechanisms of action, there was also good rationale for the combination of ipilimumab with vemurafenib, a targeted inhibitor of BRAF

mutation, which is also approved for the treatment of advanced melanoma.

This phase I study, however, was closed after use of the 2 agents at the approved doses resulted in grade 3 elevations in aminotransferase levels. Although these hepatic events were asymptomatic and reversible with drug discontinuation or glucocorticoid treatment, the findings highlight the need for appropriately conducted clinical trials to evaluate the safety of such combinations.

Ipilimumab and nivolumab are believed to target complementary immuno-inhibitory pathways leading to enhanced T-cell activation, and thus there is rational basis for combining these 2 immunotherapies. Results of a phase I study demonstrated a confirmed objective response rate of 40% (21 of 52 patients) in concurrently treated patients, which was higher than that historically seen with either agent alone, and the combination was associated with a manageable safety profile.

In view of these initial findings, a phase III study (CheckMate 067) is now investigating the safety and efficacy of nivolumab either alone or in combination with ipilimumab, or ipilimumab alone, in patients with previously untreated advanced melanoma.

The primary endpoint is OS, with secondary endpoints of progression free survival (PFS) and overall response rate (ORR). The estimated completion date for the primary outcome measure is October 2016.

A phase I, open-label, single-center, dose-escalation study was initiated to determine the safety of combining ipilimumab with prostate GVAX, (a GM-CSF gene-transfected tumor cell vaccine) in men with mCRPC.

The results of this small study showed the combination of ipilimumab (3.0 mg/kg) with GVAX to be safe and tolerable in this patient population; the most common AEs were injection site reaction, fatigue, and pyrexia. A 50% or greater decrease in prostate-specific antigen (PSA) was noted in 7 patients (25%) who had received a 3.0 mg or 5.0 mg dose of ipilimumab.

Studies are also assessing ipilimumab in combination with other prostate cancer therapies, including abiraterone/prednisone,

for their potential use in men with advanced or mCRPC.

In addition to sipuleucel-T, immunotherapies for prostate cancer include the PROSTVAC vaccines (viral-based vaccines that are thought to enhance the T-cell response to PSA).

A phase I, dose-escalation trial of PROSTVAC in combination with ipilimumab reported no dose-limiting toxicities among 30 patients, and the combination did not seem to increase immune-related AEs over ipilimumab alone.

Although the trial was too small to evaluate efficacy of the combination, 58% of patients who were chemotherapy na&iuml;ve had PSA declines, and the trial provided proof of concept for this type of combination therapy in prostate cancer.

Sipuleucel-T in combination with ipilimumab is also under investigation in a phase I study of advanced prostate cancer,

and in a phase II study with either delayed or immediate ipilimumab treatment in mCRPC.

Lung cancer is another area of investigation for immunotherapy combinations. CheckMate 012

is a phase I study investigating nivolumab as monotherapy or in combination with multiple therapies in patients with stage IIIB/IV NSCLC, including platinum-based chemotherapies (gemcitabine/cisplatin, pemetrexed/cisplatin, carboplatin/paclitaxel), antiangiogenesis therapy (bevacizumab), and epidermal growth factor receptor (EGFR)-targeted agents (erlotinib); the study will also investigate the combination of nivolumab with ipilimumab in this patient population. The use of ipilimumab in combination with mutation-targeted therapies (crizotinib or erlotinib) is being investigated in a phase I trial of patients with stage IV NSCLC with corresponding mutations; the overall goal is to evaluate a recommended phase II dose and to assess short- and long-term toxicities of these combinations.

A phase II study is also investigating the use of ipilimumab in combination with conventional chemotherapy (carboplatin and etoposide) in patients with small cell lung cancer; the primary outcome is PFS at 1 year.

A phase III study is investigating ipilimumab (or placebo) in combination with paclitaxel and carboplatin in subjects with stage IV/recurrent squamous NSCLC; the estimated primary completion date for this trial is October 2015.

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Kono K. Current status of cancer immunotherapy.

Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps.

Hodi FS, O&rsquo;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer.

Novel Immunotherapy Combinations in NSCLC. Available at:

http://www.onclive.com/peer-exchange/nsclc-therapies/Novel-Immunotherapy-Combinations-in-NSCLC

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.

Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.

van den Eertwegh AJ, Versluis J, van den Berg HP, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

Madan RA, Mohebtash M, Arlen PM, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

Peter J Sciavolino, PhD | Authors

Articles

BRAF Testing Important for Clinical Decision-Making in Metastatic Melanoma

Three Experts Weigh In on Plasma-Based Molecular Profiling in Oncology

The Next Wave in Immunotherapy: Combinations