FDA Grants Opdivo Priority Review for Small Cell Lung Cancer

Excerpt:

“The FDA has granted a priority review to a supplemental biologics license application (sBLA) for Opdivo (nivolumab) for the treatment of patients with small cell lung cancer (SCLC) with disease progression following two or more lines of therapy, according to Bristol-Myers Squibb, the manufacturer of the PD-1 inhibitor.

“The sBLA is based on data from the phase 1/2 CheckMate-032 trial, in which single-agent Opdivo led to a median overall survival (OS) of 4.4 months and a one-year OS rate of 33 percent in patients with progressive SCLC following one or more prior lines of therapy. Under the priority review, the FDA is scheduled to make its decision by Aug. 16, 2018.”

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Predicting If an Immune Checkpoint Drug Will Work


Drugs that activate the immune system to attack cancer in a process known as immune checkpoint blockade (ICB) are a focus of intense investigation. A number of them are already approved by the U.S. Food and Drug Administration (FDA) for various cancers; namely, the anti-CTLA4 antibody ipilimumab (Yervoy), two anti-PD-1 antibodies: pembrolizumab (Keytruda) and nivolumab (Opdivo), and three anti-PD-L1 drugs: atezolizumab (Tecentriq), avelumab (Bavencio) and durvalumab (Imfinzi). These ICB drugs have the potential to induce durable cancer regressions, but the majority of cancer patients just do not respond to them at all.

Biomarkers, signature molecules in the blood or other tissue, can sometimes be used to predict a patient’s response to a given treatment. But no reliable biomarkers exist for ICB, and this is a serious concern. Patients who may really benefit from ICB could be overlooked, and patients who are not likely to respond may receive useless (and very expensive) ICB treatment.

Most potential response predictors that have already been identified are not yet useful for one or all of the following reasons: they are not extensively validated, their significance is still uncertain and may differ from one cancer (or even one patient) to another, or they are technically challenging for routine use. These markers are addressed below. Continue reading…


Nivolumab/Ipilimumab Doubles Intracranial Response in Melanoma Brain Mets

Excerpt:

“The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) induced an intracranial response of 46% in melanoma patients with asymptomatic, untreated brain metastases. The intracranial response rate (ICR) with nivolumab monotherapy was 20%.

“Investigators observed a response in 16 of 35 evaluable patients treated with 1 mg/kg of nivolumab combined with 3 mg/kg of ipilimumab every 3 weeks for 4 doses, then 3 mg/kg of nivolumab every 2 weeks (cohort A). In contrast, only 5 of 25 evaluable patients randomly assigned to 3 mg/kg of intravenous nivolumab every 2 weeks (cohort B) showed a response.”

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New Immunotherapy for Lung Cancer Shows Promise of Success

Excerpt:

“In a groundbreaking development, results from a recent clinical trial to treat lung cancer show that a novel immunotherapy combination is surprisingly effective at controlling the disease’s progression. The study, published April 4 in the journal The Lancet Oncology, focused on non-small cell lung cancer, which is the most common form of lung cancer.”

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No Benefit of PD-1/PD-L1 Inhibitors in Metastatic EGFR Mutated Non-Small Cell Lung Cancer

Excerpt:

“Immune checkpoint inhibitors have revolutionized the treatment of metastatic non-small cell lung cancer (NSCLC). In patients progressing on first-line therapy, immunotherapy with the PD-1/PD-L1 inhibitors pembrolizumab, nivolumab, and atezolizumab has become standard second-line therapy. While these agents are associated with durable responses and long-term improvements in overall survival (OS), only a small proportion of patients respond to treatment. Relatively little is known about the factors that predispose patients to response on checkpoint inhibitors, and there is an unmet need for improved patient selection criteria.”

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New Developments in Melanoma Treatment


Neoadjuvant (before-surgery) treatments for resectable melanoma

Neoadjuvant treatments are the mainstay in the care of patients with breast, colon, and other cancers, but have not traditionally been used in melanoma. This has changed now, with the publication of a report showing that patients with resectable stage III or IV BRAF-mutant melanoma benefit from treatment with the BRAF/MEK inhibitor drugs dabrafenib and trametinib prior to (and continued after) surgery. The randomized clinical trial that produced these findings was small, but the benefits were so obvious that the researchers had to close the control group—those patients who received a placebo instead of neoadjuvant treatment. 71% of the 14 patients in the trial who received BRAF/MEK inhibitors prior to surgery were disease-free after 18 months, whereas all seven patients in the control group experienced a recurrence. The trial is continuing without the control group: all patients will receive treatment prior to surgery

Adjuvant (after-surgery) treatments

Melanoma patients whose tumors are surgically removed experience a very high rate of recurrence. Until recently, adjuvant treatments to prevent recurrences were limited to the drug interferon alpha-2B and, more recently, ipilimumab (brand name Yervoy), an anti-CTLA-4 immune checkpoint drug approved by the U.S. Food and Drug Administration (FAD) for adjuvant treatment in 2015. Interferon treatment is extremely harsh, with many adverse effects, and is not often used anymore. Yervoy is often associated with autoimmune side effects, which are sometimes quite serious.

Enter nivolumab (Opdivo) the anti-PD-1 checkpoint drug approved by the FDA to treat metastatic melanoma and other cancers. A clinical trial showed that the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% compared to 52.7% for ipilimumab (Yervoy) in patients with resected stage IIIB/C or IV melanoma. This amounts to a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor. Not the least important factor is the much lower rate of side effects seen with nivolumab compared to ipilimumab. Nivolumab is now approved by the FDA as an adjuvant treatment after surgical resection of melanoma.

Pembrolizumab, a competing anti-PD-1 drug, also showed encouraging results in a randomized trial for stage III melanoma. The stakes in this trial were lower, since the control arm received a placebo (not ipilimumab!). Risk reduction was 43%, according to preliminary results of the trial.

For patients with BRAF-mutant stage III melanoma, adjuvant treatment with the BRAF/MEK inhibitors dabrafenib and trametinib was just recently granted a priority review by the FDA, signaling a likely approval soon. Recurrence-free 3-year survival was 58% for the combination versus 39% for placebo.

New treatments for metastatic melanoma

A Knowledge Blog post from last summer described new combination treatments for metastatic melanoma. There have been significant developments since then.

Several trials combined PD-1 blockers (pembrolizumab or nivolumab) with small molecules known as IDO inhibitors. The latter help shut down the activity of immune system cells known as regulatory T cells (T regs), which dampen the immune response triggered by anti-PD-1 drugs. Combination of pembrolizumab with the IDO inhibitor epacadostat increased the rate of responses to pembrolizumab from 32% to 56%. This is very comparable to the response rate seen with the FDA-approved combination of nivolumab and ipilimumab. However, the significant toxicities seen with addition of ipilimumab are not observed when IDO inhibitors are added. Several other competing IDO inhibitors are currently in trials with both pembrolizumab and nivolumab. Importantly, there is also hope that these drug combinations may abolish resistance to PD-1 blockers in previously treated melanoma patients.

Another promising combination has been tested in a small clinical trial of nivolumab with NKTR-214, a specifically modified form of the protein IL-2, which is a strong activator of the immune system. High-dose IL-2 is a drug that has long been approved for metastatic melanoma but is rarely used because of the extremely serious adverse effects. NKTR-214 is a modified (PEGylated) IL-2 that has much reduced side effects, and does not activate inhibitory T regs. Clinical trial results have been released for 11 melanoma patients treated with the combination. Of the patients enrolled, 73% have experienced objective responses, which is obviously much higher than what is seen with nivolumab alone. This trial is now enrolling patients who have or have not already been treated with immune drugs.

Patients who were treated with anti-PD-1 drugs and experience progression may consider enrolling in trials that add relatlimab (an anti-LAG3 immune drug) to nivolumab. In a trial that enrolled heavily pretreated patients who failed on previous treatment with anti-PD-1 drugs, the rate of response was 11.5%, but many more patients (38%) have achieved stable disease. The presence of LAG3 protein (but not PD-L1 protein) in the tumors was predictive of response.

There are other new drugs to watch. TLR9 agonists (activators) have shown early promising results in melanoma. TLR is a group of receptors that are strongly involved in innate immunity. A recent publication showed that intratumoral injection of a TLR9 activator with an antibody to OX40 (a protein on T cells) has extraordinary activity in a mouse cancer model. Trials that combine anti-OX40 and TLR9 agonists are forthcoming. However, two TLR9 agonists, SD-101 and IMO-2125, have shown very promising results in combination with anti-PD-1 or anti-CTLA4 drugs.

The other drug with early promise is ImmunoPulse IL-12 (pIL-12). In combination with pembrolizumab, it induced responses in 43% of patients who had not been previously treated with immune drugs. The important point is that patients in this trial were specifically selected to have a tumor profile that is associated with lack of response to pembrolizumab. pIL-12 is injected into tumors, so this intervention is appropriate for patients who have injectable tumors.

New BRAF/MEK inhibitors for melanoma have emerged: encorafenib and binimetinib produced a 3-year overall survival rate that is twice as high as seen with vemurafenib, a BRAF inhibitor. The comparison is not exactly meaningful because vemurafenib is not used as a single drug in BRAF-mutant melanoma these days, but this phase III trial was initiated back in 2013, prior to the approval of other BRAF/MEK combinations. The new combination may be approved mid-2018.

The triplet combinations for BRAF-mutant melanoma should be mentioned (immune plus targeted drugs). A trial that combined dabrafenib and trametinib with pembrolizumab reported early success, with a confirmed response rate of 67% in 15 patients who received the combination.


Frontline Nivolumab/Ipilimumab Improves PFS in High TMB NSCLC

Excerpt:

“The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) improved progression-free survival (PFS) compared with chemotherapy in treatment-naïve patients with high tumor mutation burden (TMB) non–small cell lung cancer (NSCLC).

“Bristol-Myers Squibb (BMS), the manufacturer of both immunotherapies, announced the preliminary findings from part 1a of the phase III CheckMate-227 trial in a press release. The company did not report any further data.”

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Adjuvant Nivolumab Granted FDA Approval for Melanoma

Excerpt:

“Nivolumab (Opdivo) has received FDA approval for the adjuvant treatment of patients with completely resected melanoma with lymph node involvement or metastatic disease.

“The approval is based on findings of the randomized phase III CheckMate-238 trial, in which the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% (95% CI, 61.8%-70.6%) compared with 52.7% (95% CI, 47.8%-57.4%) for ipilimumab (Yervoy) in patients with stage IIIB/C or stage IV melanoma after surgery. There was a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor (HR, 0.65; 95% CI, 0.53-0.80; P <.0001).”

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Adjuvant Nivolumab Granted FDA Approval for Melanoma

Excerpt:

“Nivolumab (Opdivo) has received FDA approval for the adjuvant treatment of patients with completely resected melanoma with lymph node involvement or metastatic disease.

“The approval is based on findings of the randomized phase III CheckMate-238 trial, in which the recurrence-free survival (RFS) rate at 18 months with nivolumab was 66.4% (95% CI, 61.8%-70.6%) compared with 52.7% (95% CI, 47.8%-57.4%) for ipilimumab (Yervoy) in patients with stage IIIB/C or stage IV melanoma after surgery. There was a 35% reduction in the risk of recurrence or death with the PD-1 inhibitor versus the CTLA-4 inhibitor (HR, 0.65; 95% CI, 0.53-0.80; P <.0001).”

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