What is the efficacy and safety of combining Pembrolizumab (Keytruda) and Paclitaxel for cancer treatment?

Pembrolizumab + Paclitaxel in Cancer Treatment

The combination of pembrolizumab with carboplatin and paclitaxel (or nab-paclitaxel) is a standard first-line treatment option for metastatic squamous non-small-cell lung cancer (NSCLC) with performance status 0-1, demonstrating significant overall survival benefit (median OS 17.1 vs 11.6 months, HR 0.71) across all PD-L1 expression levels. 1

Evidence-Based Indications by Cancer Type

Metastatic Squamous NSCLC (Strongest Evidence)

For patients with PS 0-1 and metastatic squamous NSCLC without contraindications to immunotherapy, pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel should be considered the standard choice. 1

• The KEYNOTE-407 trial (N=559) demonstrated improved OS: median 17.1 versus 11.6 months (HR 0.71,95% CI 0.58-0.88) when pembrolizumab was added to carboplatin-(nab)-paclitaxel. 1
• The survival benefit was preserved across PD-L1 expression strata, though statistical significance diminished in subgroups. 1
• For patients with PD-L1 <1%, the recommendation is now graded as "weak" due to modest benefit in this subgroup (median OS 15.0 vs 11.0 months; HR 0.83,95% CI 0.61-1.13). 1
• Treatment consists of 4 cycles of pembrolizumab 200 mg every 3 weeks with chemotherapy, followed by pembrolizumab maintenance. 1

Triple-Negative Breast Cancer (TNBC)

For early-stage TNBC, pembrolizumab combined with nab-paclitaxel followed by anthracycline-based chemotherapy achieves pathological complete response (pCR) rates of 66-72%, representing an effective neoadjuvant approach. 2

• The NeoImmunoboost trial demonstrated pCR rate of 66.0% (95% CI: 51.2%-78.8%) in the intention-to-treat population and 71.8% in the per-protocol population. 2
• For metastatic TNBC in 1st/2nd line setting, pembrolizumab with weekly paclitaxel (80 mg/m² weekly) showed 29% objective response rate (95% CI: 10-61%). 3
• Pembrolizumab with flat-dose capecitabine showed 43% objective response rate (95% CI: 18-71%) in metastatic TNBC. 3
• Both regimens met pre-specified safety endpoints (paclitaxel: 87%; capecitabine: 100%). 3

Non-Squamous NSCLC

For non-squamous NSCLC, pembrolizumab is preferentially combined with pemetrexed plus platinum rather than paclitaxel. 1

• The KEYNOTE-189 trial showed superior outcomes with pembrolizumab-pemetrexed-platinum (median OS not reached vs 11.3 months, HR 0.49). 1
• Atezolizumab-bevacizumab-carboplatin-paclitaxel is an alternative option for non-squamous NSCLC (median OS 19.5 vs 14.7 months, HR 0.80). 1

Treatment Administration and Duration

• Dosing: Pembrolizumab 200 mg IV every 3 weeks with carboplatin and paclitaxel (or nab-paclitaxel). 1, 4
• Chemotherapy cycles: 4 cycles of combination therapy followed by pembrolizumab maintenance for up to 31 additional cycles. 1, 5
• Paclitaxel dosing: Standard paclitaxel or nab-paclitaxel can be used; nab-paclitaxel may be preferred in patients with greater risk of neurotoxicity or hypersensitivity to standard paclitaxel. 1

Safety Profile and Toxicity Management

Common Adverse Reactions (≥20%)

The most frequent adverse reactions include peripheral neuropathy (58%), alopecia (56%), fatigue (48-70%), nausea (44-67%), and hematologic toxicities. 4

• Peripheral neuropathy occurs in 41-58% of patients (Grade 3-4: 3.3-4.2%). 4
• Neutropenia: 75-88% all grades, 32-50% Grade 3-4. 4
• Anemia: 88-97% all grades, 20-31% Grade 3-4. 4
• Thrombocytopenia: 54-65% all grades, 8-19% Grade 3-4. 4

Serious Adverse Reactions

• Febrile neutropenia occurred in 15% of patients in the KEYNOTE-522 trial. 4
• Fatal adverse reactions occurred in 1.4-4.6% of patients across trials. 4
• Discontinuation due to adverse reactions: 7-20% of patients. 4
• Treatment interruption required in 43-66% of patients, most commonly for hematologic toxicities. 4

Immune-Related Adverse Events

Monitor for immune-related adverse events including hypothyroidism (20-22%), pneumonitis, colitis, and hepatotoxicity. 6, 4

• Hypothyroidism occurs in 20% of patients receiving pembrolizumab-chemotherapy combinations. 4
• Increased ALT/AST: 44-71% all grades, 2.1-11% Grade 3-4. 4

Quality of Life Considerations

Pembrolizumab plus chemotherapy maintains or improves health-related quality of life compared to chemotherapy alone, with significant improvements at weeks 9 and 18. 5

• Global health status/quality of life scores improved with pembrolizumab-combination (LS mean change at week 18: +4.3) versus deterioration with placebo-combination (-0.57), with between-group difference of 4.9 (95% CI 1.4-8.3, P=0.0060). 5
• Time to deterioration in respiratory symptoms (cough, chest pain, dyspnea) was not significantly different but trended favorably (HR 0.79,95% CI 0.58-1.06). 5

Patient Selection and Biomarkers

PD-L1 Expression

• For squamous NSCLC, benefit is observed across all PD-L1 expression levels, though more robust in PD-L1 ≥1%. 1
• Single-agent pembrolizumab is preferred for PD-L1 ≥50% (median OS 30 vs 14 months compared to chemotherapy). 1
• For PD-L1 <1%, combination therapy is recommended over monotherapy, though with weaker evidence. 1

Additional Biomarkers

Response correlates with clinical PD-L1 score, H&E stromal tumor-infiltrating lymphocyte score, and novel spatial biomarkers including lymphocyte spatial skewness. 3

• A 27-gene IO score showed association with response in TNBC. 3
• Non-receipt of prior chemotherapy predicts better response. 3

Critical Contraindications and Precautions

• Molecular testing required: Exclude EGFR and ALK mutations before initiating immunotherapy in NSCLC. 1
• Performance status: Limit to PS 0-1 for combination therapy. 1
• Avoid in squamous histology with bevacizumab: Risk of hemoptysis contraindicates bevacizumab in squamous NSCLC. 1
• Baseline organ function: Evaluate complete blood count, renal function, and liver function tests prior to initiation. 7

Common Pitfalls to Avoid

• Do not delay molecular testing: EGFR/ALK testing must be completed before starting immunotherapy in NSCLC to avoid inappropriate treatment. 1
• Do not use pembrolizumab-paclitaxel as first choice in non-squamous NSCLC: Pembrolizumab-pemetrexed-platinum is the preferred regimen for non-squamous histology. 1
• Monitor for lymphodepletion: Both paclitaxel and capecitabine combinations cause significant peripheral leukocyte contraction, highlighting competing immunostimulatory versus lymphotoxic effects. 3
• Recognize immune-related toxicities early: Distinguish immune-related adverse events from chemotherapy toxicities to guide appropriate management. 6, 4