Author: RR

TECVAYLI® (Teclistamab-cqyv)

RR

The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory Multiple Myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. TECVAYLI® is a product of Janssen Biotech, Inc.

RETEVMO® (Selpercatinib)

RR

The FDA on September 21, 2022, granted accelerated approval to RETEVMO® (Selpercatinib) for adult patients with locally advanced or metastatic solid tumors with a REearranged during Transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. RETEVMO® is a product of Eli Lilly and Company.

Neoadjuvant Chemotherapy, Endocrine Therapy and Targeted Therapy for Breast Cancer: ASCO Updated Guideline

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 290,560 new cases of breast cancer were diagnosed in 2022 and about 43,780 individuals died of the disease, largely due to metastatic recurrence.

Adjuvant or postoperative systemic therapy is the mainstay of treatment for early-stage breast cancer, to eradicate micrometastatic disease and reduce the likelihood of metastatic disease. Neoadjuvant refers to the use of systemic therapy prior to surgery. Neoadjuvant therapy was initially used in breast cancer for the treatment of inoperable, locally advanced disease. Subsequently, multiple studies of both chemotherapy and endocrine therapy have shown that neoadjuvant treatment can increase the likelihood of breast-conserving surgery, reduce the extent and morbidity of curative surgery, establishing neoadjuvant treatment as a viable option in patients with operable disease. Further, interest in neoadjuvant therapy has focused on examining the role of response to neoadjuvant treatment as a predictive marker for benefit in long term outcomes.

ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and the purpose of this guideline is to develop recommendations concerning the optimal use of systemic neoadjuvant therapy, including chemotherapy, endocrine therapy, and targeted therapy for patients with invasive breast cancer.

Guideline Question
What is the optimal use of neoadjuvant therapy for women with invasive, nonmetastatic breast cancer?

CLINICAL QUESTION 1
Which patients with breast cancer are appropriate candidates for neoadjuvant systemic therapy?

Recommendation 1.1.
Neoadjuvant chemotherapy is the treatment of choice for patients with inflammatory breast cancer or those with unresectable or locally advanced disease at presentation whose disease may be rendered resectable with neoadjuvant treatment
Recommendation 1.2.
Tumor histology, grade, stage and estrogen, progesterone, and HER2 expression should routinely be used to guide clinical decisions as to whether or not to pursue neoadjuvant chemotherapy. There is insufficient evidence to support the use of other immunochemical markers, morphological markers (eg, tumor-infiltrating lymphocytes) or genomic profiles to guide a clinical decision as to whether or not to pursue neoadjuvant chemotherapy
Recommendation 1.3.
Neoadjuvant systemic therapy should be offered to patients with high-risk HER2-positive or triple-negative breast cancer (TNBC) in whom the finding of residual disease would guide recommendations related to adjuvant therapy
Recommendation 1.4.
Neoadjuvant systemic therapy may be offered to reduce the extent of surgery (breast-conserving surgery and axillary lymph node dissection). Chemotherapy with or without targeted therapy, or endocrine therapy (if hormone receptor–positive [HR-positive]) may be offered
Recommendation 1.5.
In patients for whom a delay in surgery is preferable (eg, for genetic testing required for surgical treatment decision making, to allow time to consider reconstructive options) or unavoidable, neoadjuvant systemic therapy may be offered

CLINICAL QUESTION 2
How should response be measured in patients receiving neoadjuvant chemotherapy?

Recommendation 2.1.
Patients receiving neoadjuvant therapy should be monitored for response with clinical examination at regular intervals. Breast imaging may be used to confirm clinical suspicion of progression and for surgical planning. When imaging is used, the modality that was most informative at baseline-mammography, ultrasound, or magnetic resonance imaging—should be used at follow-up
Recommendation 2.2.
Blood- and tissue-based biomarkers should not be used for monitoring patients receiving neoadjuvant therapy
Recommendation 2.3.
Pathologic complete response (pCR), defined as absence of invasive disease in breast and lymph nodes, should be used to measure response to guide clinical decision making

CLINICAL QUESTION 3
What neoadjuvant treatment is recommended for patients with HR-positive/HER2-negative breast cancer?

Recommendation 3.1.
Neoadjuvant chemotherapy can be used instead of adjuvant chemotherapy in any patient with HR-positive, HER2-negative breast cancer in whom the chemotherapy decision can be made without surgical pathology data and/or tumor-specific genomic testing
Recommendation 3.2.
For postmenopausal patients with HR-positive/HER2-negative disease, neoadjuvant endocrine therapy with an aromatase inhibitor may be offered to increase locoregional treatment options. If there is no intent for surgery, endocrine therapy may be used for disease control
Recommendation 3.3.
For premenopausal patients with HR-positive/HER2-negative early-stage disease, neoadjuvant endocrine therapy should not be routinely offered outside of a clinical trial (Type: evidence-based; benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

CLINICAL QUESTION 4
What neoadjuvant treatment is recommended for patients with HER2-positive disease?

Recommendation 4.1.
Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy with an anthracycline and taxane or non–anthracycline-based regimen in combination with trastuzumab. Pertuzumab may be used with trastuzumab in the neoadjuvant setting
Recommendation 4.2.
Patients with T1a N0 and T1b N0, HER2-positive disease should not be routinely offered neoadjuvant chemotherapy or anti-HER2 agents outside of a clinical trial

CLINICAL QUESTION 5
What neoadjuvant systemic therapy regimens are recommended for patients with TNBC?

Recommendation 5.1.
Patients with TNBC who have clinically node-positive and/or at least T1c disease should be offered an anthracycline and taxane-containing regimen in the neoadjuvant setting
Recommendation 5.2.
Patients with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy outside of a clinical trial
Recommendation 5.3.
Carboplatin may be offered as part of a neoadjuvant regimen in patients with TNBC to increase likelihood of pCR. The decision to offer carboplatin should take into account the balance of potential benefits and harms
Recommendation 5.4. (UPDATED ASCO RECOMMENDATION FROM 2022: GUIDELINE RAPID RECOMMENDATION UPDATE)
For patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage TNBC, the Panel recommends use of pembrolizumab (200 mg once every 3 weeks or 400 mg once every 6 weeks) in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery. Adjuvant pembrolizumab may be given either concurrent with or after completion of radiation therapy. Given that irAEs associated with pembrolizumab therapy can be severe and permanent, careful screening for and management of common toxicities are required.

The guideline panel addressed some of the questions that clinicians may encounter as they incorporate these recommendations into clinical practice.

QUESTION: SHOULD PEMBROLIZUMAB BE CONTINUED IN PATIENTS WHO ACHIEVE pCR AFTER NEOADJUVANT CHEMOTHERAPY PLUS PEMBROLIZUMAB?
The panel supports continuation of pembrolizumab in the adjuvant setting in all patients while awaiting data from other trials addressing this question.

QUESTION: CAN A CHEMOTHERAPY REGIMEN DIFFERENT FROM THE ONE USED IN KEYNOTE-522 BE USED WITH PEMBROLIZUMAB?
The panel supports the use of the full KEYNOTE-522 regimen. However, if a patient experiences toxicity, it is not unreasonable to dose reduce or discontinue the drug. In patients with TNBC who have contraindications to anthracycline therapy and are being considered for regimens such as docetaxel and cyclophosphamide, it would be reasonable to add pembrolizumab to their regimen.

QUESTION: SHOULD ADJUVANT CAPECITABINE BE ADMINISTERED WITH PEMBROLIZUMAB IN PATIENTS WHO FAIL TO ACHIEVE pCR WITH PEMBROLIZUMAB-BASED NEOADJUVANT THERAPY?
Patients with TNBC who have residual disease after neoadjuvant chemotherapy are currently offered adjuvant capecitabine chemotherapy on the basis of improved survival shown in CREATE-X trial. It is reasonable to administer capecitabine concurrently or sequentially in patients at high risk of recurrence although the long-term safety of this combination is not known.

QUESTION: SHOULD OLAPARIB BE ADDED TO PEMBROLIZUMAB FOR gBRCA1m AND/OR gBRCA2m CARRIERS WITH TNBC WHO HAVE RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY?
Patients with TNBC are more likely to harbor a gBRCA1m and/or gBRCA2m, and such mutations have been reported in about 15% of patients with TNBC. The use of adjuvant pembrolizumab and olaparib concurrently or sequentially can be considered for eligible patients. The relative risks and benefits of a concurrent approach should be weighed, as the long-term safety of these combinations is not known.

QUESTION: SHOULD OTHER CHECKPOINT INHIBITORS BE USED IN THE NEOADJUVANT SETTING INSTEAD OF PEMBROLIZUMAB?
As only pembrolizumab has received regulatory approval, the panel does not recommend use of alternate immunotherapeutic agents.

QUESTION: SHOULD ADJUVANT PEMBROLIZUMAB BE USED IN PATIENTS WITH RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY WITHOUT PEMBROLIZUMAB?
There are currently no data to support adjuvant pembrolizumab use in patients who did not receive neoadjuvant pembrolizumab.

In summary, addition of pembrolizumab to chemotherapy in the neoadjuvant setting followed by continuation in the adjuvant setting is the new standard of care for patients with high-risk TNBC as defined in KEYNOTE-522.

Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer Guideline Expert Panel. Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Korde LA, Somerfield MR, Hershman DL, et al. J Clin Oncol. 2022;40:1696-1698.

Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. Korde LA, Somerfield MR, Carey LA, et al. DOI: 10.1200/JCO.20.03399 Journal of Clinical Oncology 39, no. 13 (May 01, 2021) 1485-1505.

Tumor-Infiltrating Lymphocyte Therapy in Advanced Refractory Melanoma

RR

SUMMARY: The American Cancer Society estimates that in 2022, about 99,780 new cases of melanoma of the skin were diagnosed in the United States and 7,650 people died of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. They are therefore frequently used first-line treatment in patients with metastatic melanoma.

Over 50% of untreated patients receiving a combination of PD-1 and CTLA-4 inhibitors are alive after five years. However, combination immunotherapy with YERVOY® and OPDIVO® is associated with a high incidence of severe adverse events and is currently recommended primarily for a subgroup of patients with poor prognostic factors such as a high serum LDH levels or liver or brain metastases. Approximately 50% of melanomas harbor BRAF V600E mutation and are often treated with a combination of BRAF and MEK inhibitors. This combination is associated with a high response, but resistance develops in most patients over time. YERVOY® is presently often used as second line therapy, but only 15-30% of patients benefit from this intervention. There is an unmet need for this group of patients.

Adoptive immunotherapy, also known as cellular immunotherapy, is a form of treatment in which naturally occurring or gene-engineered T cells with antitumor activity are transferred to a tumor-bearing host to eliminate cancer. These killer T cells bind to antigens on the surface of cancer cells and destroy them. Cellular immunotherapies include Tumor-Infiltrating Lymphocyte (TIL) Therapy, Engineered T Cell Receptor (TCR) Therapy, Chimeric Antigen Receptor (CAR) T Cell Therapy and Natural Killer (NK) Cell Therapy.

Adoptive immunotherapy with Tumor-Infiltrating Lymphocytes (TILs) is a personalized autologous therapy in which lymphocytes which have infiltrated the tumor are expanded in vitro and administered intravenously following nonmyeloablative, lymphodepleting chemotherapy, and supported by the IV administration of Interleukin-2 (IL-2) to enhance the in vivo expansion of the cells and augment antitumor responses. In contrast to Lymphokine-Activated Killer cells (LAK), human TILs demonstrate cytolytic specificity against only the tumor from which they were derived or against closely related tumors, and in preclinical models have proved to be 50 to 100 times more potent than LAK cells. Evidence of clinical activity of TIL therapy in patients with advanced melanoma was initially reported by Rosenberg and colleagues in the 1990s and subsequent Phase 1-2 trials showed responses in 30-70% of patients, with responses noted even among those who had disease progression while receiving anti-PD1 treatment. Nonetheless, there has been no direct comparison of TILs with standard treatment.

This multicenter, open-label, Phase III, randomized trial was conducted to compared TILs with Yervoy® as first or second-line treatment in patients with advanced melanoma. In this study, a total of 168 patients with unresectable Stage IIIC or IV melanoma were randomly assigned in a 1:1 ratio to receive either TILs (N=84) or YERVOY® (N=84). Patients assigned to receive TILs underwent metastasectomy for the retrieval and expansion of TILs, followed by inpatient administration of nonmyeloablative, lymphodepleting chemotherapy, which consisted of Cyclophosphamide 60 mg/kg IV QD for 2 days and Fludarabine 25 mg/m2 IV QD for 5 days, single adoptive transfer of 5×109 to 2×1011 TILs intravenously, and subsequent high-dose IL-2, 600,000 IU/kg IV every 8 hours, for a maximum of 15 doses. Patients in the YERVOY® group received 3 mg/kg IV every 3 weeks, for a maximum of 4 doses. Administration of YERVOY® could be delayed or discontinued if adverse events occurred, and no dose reductions were allowed. Both treatment groups were well balanced and 86% of patients were refractory to PD-1 inhibitor therapy, mostly adjuvant or first line therapy. The median patient age was 59 years and patients were stratified according to BRAF V600-mutation status, line of treatment, and treatment center. The Primary end point was Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR), Complete Response (CR), Overall Survival (OS), Health-Related Quality of Life and Safety.The median follow-up was 33.0 months.

The median PFS was 7.2 months in the TIL group and 3.1 months in the YERVOY® group (HR=0.50;P<0.001).The Objective Response Rate was 49% in the TIL group and 21% in the YERVOY® group, with a Complete Response rate of 20% in the TIL group and 7% in the YERVOY® group, with durable Complete Responses in both treatment groups. The median Overall Survival was 25.8 months in the TIL group and 18.9 months in the YERVOY® group(HR=0.83). The 2-year OS was 54.3% in the TIL group and 44.1% in the YERVOY® group. Treatment-related adverse events of Grade 3 or higher occurred in all patients in the TIL group and in 57% of those in the YERVOY® group, and these events were mainly chemotherapy-related myelosuppression. Treatment-related serious adverse events occurred in 15% of the patients in the TIL group and 27% of those in the YERVOY® group.

It was concluded that in patients with advanced melanoma including those patients refractory to PD-1 inhibitor therapy, treatment with TILs was associated with significantly longer Progression Free Survival than treatment with YERVOY®.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. Rohaan MW, Borch TH, Van den Berg JH, et al. N Engl J Med 2022; 387:2113-2125